ClinVar Genomic variation as it relates to human health
NM_000169.3(GLA):c.427G>A (p.Ala143Thr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(1); Likely pathogenic(5); Uncertain significance(16); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000169.3(GLA):c.427G>A (p.Ala143Thr)
Variation ID: 10748 Accession: VCV000010748.69
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq22.1 X: 101401752 (GRCh38) [ NCBI UCSC ] X: 100656740 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 28, 2015 May 12, 2024 Dec 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000169.3:c.427G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000160.1:p.Ala143Thr missense NM_001199973.2:c.300+6295C>T intron variant NM_001199974.2:c.177+9930C>T intron variant NR_164783.1:n.449G>A non-coding transcript variant NC_000023.11:g.101401752C>T NC_000023.10:g.100656740C>T NG_007119.1:g.11212G>A LRG_672:g.11212G>A LRG_672t1:c.427G>A P06280:p.Ala143Thr - Protein change
- A143T
- Other names
- -
- Canonical SPDI
- NC_000023.11:101401751:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on protein activity Variation Ontology [VariO:0053]
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00039
Trans-Omics for Precision Medicine (TOPMed) 0.00041
The Genome Aggregation Database (gnomAD), exomes 0.00055
Exome Aggregation Consortium (ExAC) 0.00077
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GLA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
6 | 1239 | |
RPL36A-HNRNPH2 | - | - | - |
GRCh38 GRCh37 |
- | 1270 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (18) |
criteria provided, conflicting classifications
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Dec 13, 2023 | RCV000011495.49 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 3, 2022 | RCV000157242.13 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jul 21, 2023 | RCV000211872.22 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Oct 27, 2023 | RCV000224064.34 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 16, 2023 | RCV000618614.12 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV000845429.11 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Mar 06, 2015)
|
criteria provided, single submitter
Method: clinical testing
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Fabry's disease
Affected status: unknown
Allele origin:
unknown
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000257640.2
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987502.1
First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 |
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Uncertain significance
(Feb 08, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198197.5
First in ClinVar: Jan 30, 2015 Last updated: Jul 06, 2020 |
Comment:
Variant classified as Uncertain Significance - Favor Benign. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Classified by NVA lite … (more)
Variant classified as Uncertain Significance - Favor Benign. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Classified by NVA lite in 2018. 23 papers in HGMD are conflicting. Classifications in clinvar are conflicting: LP (EGL, CHOP), P (Integrated, CMHC), VUS (7 submitters). Gnomad: 0.095% (88 alleles; 26 hemizygotes). 29 hemi males (BF: in gnomad); variant has been associated with mild phenotype (less)
Number of individuals with the variant: 3
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Uncertain significance
(Jan 22, 2020)
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criteria provided, single submitter
Method: curation
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Fabry disease
(X-linked inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422640.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022
Comment:
X-linked inheritance (primarily recessive with milder female expression)
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Comment:
The p.Ala143Thr variant in GLA has been reported in the literature in many individuals with non-classic Fabry disease (PMID: 9100224, 22805550, 21549080, 25040344, 23219219, 27142856, … (more)
The p.Ala143Thr variant in GLA has been reported in the literature in many individuals with non-classic Fabry disease (PMID: 9100224, 22805550, 21549080, 25040344, 23219219, 27142856, 23430526, 23935525), and has been identified in 0.095% (88/92769) of European (non-Finnish) chromosomes, including 26 hemizygous , 0.039% (11/28049) Latino chromosomes, including 2 hemizygotes, 0.016% (3/19041) African chromosomes, including 1 hemizygote, 0.013% (1/7665) Ashkenazi Jewish chromosomes, and 0.0054% (1/18649) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs104894845). This variant has also been reported in ClinVar as likely pathogenic by EGL Genetic Diagnostics, Division of Genomic Diagnostics (The Children's Hospital of Philadelphia), and Integrated Genetics/Laboratory Corporation of America, as a VUS by the Laboratory for Molecular Medicine (Partners Healthcare), Blueprint Genetics, Invitae, ARUP Laboratories, Ambry Genetics, Bioscientia Institut fuer Medizinische Diagnostik GmbH, and GeneReviews, and as Pathogenic by Center for Pediatric Genomic Medicine and OMIM (Variation ID: 10748). In vitro functional studies provide some evidence that the p.Ala143Thr variant may impact protein function (PMID: 21598360, 16595074, 17532296, 16773563, 25040344, 23935525). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ala143Thr variant is uncertain. ACMG/AMP Criteria applied: PM5, BS1, PS3_moderate, PP3 (Richards 2015). (less)
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Likely pathogenic
(Dec 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440522.2
First in ClinVar: Oct 31, 2020 Last updated: Dec 24, 2022 |
Comment:
_x000D_ Criteria applied: PS3, PS4_MOD, PM5, PP3
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Uncertain significance
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768639.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3C. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3C. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Fabry disease (MIM#301500). Truncating variants in the last exon have been reported with a dominant negative mechanism, while those predicted to undergo nonsense mediated decay been reported with a loss of function mechanism. Missense variants have been reported with both aforementioned mechanisms. Gain of function has also been suggested, however more evidence is required (PMID: 8878432; PMID: 31613176). (I) 0109 - This gene is associated with X-linked disease. Both males and females have been reported with fabry disease, though the latter are more rarely reported and tend to have milder disease (OMIM, PMID: 31613176). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a condition (75 heterozygotes, 0 homozygotes, 29 hemizygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated alpha galactosidase A domain (PDB, NCBI). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.Ala143Pro) has been reported multiple times as pathogenic and likely pathogenic, and in patients with classic fabry disease (ClinVar, fabry-database.org). Other alternative changes (p.Ala143Ser, p.Ala143Val) have been reported as VUS (ClinVar, PMID: 31956509). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been described as pathogenic and likely pathogneic, but more recently as likely benign and as a VUS (ClinVar). Fabry disease databases classify this variant as benign and as a polymorphism (dbFGP.org, fabry-database.org). Published literature has reported this variant in patients with fabry disease or cardiomyopathy, and described it as a likely neutral variant, a modifier and as a late-onset variant with incomplete sex- and age- dependant penetrance (PMID: 27142856; PMID: 29867742; PMID: 31949022). (I) 1010 - Functional evidence for this variant is inconclusive. Patients with this variant have been repeatedly reported with decreased but variable, enzyme activity. Residual enzyme activity was not consistently below the diagnostic threshold (PMID: 31949022, PMID: 27142856). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Uncertain significance
(Nov 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000543765.8
First in ClinVar: Apr 16, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 143 of the GLA protein (p.Ala143Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 143 of the GLA protein (p.Ala143Thr). This variant is present in population databases (rs104894845, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with late-onset, mild, or non-classic Fabry disease phenotype with or without Gb-3 storage on cardiac or renal biopsy as well as unaffected adult male relatives (PMID: 9100224, 16773563, 21549080, 22805550, 23219219, 23430526, 23935525, 25040344, 27142856, 28799081). ClinVar contains an entry for this variant (Variation ID: 10748). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GLA protein function. Experimental studies have shown that this missense change affects GLA function (PMID: 9100224, 21549080, 22805550, 23219219, 23430526, 23935525, 25040344, 27142856). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Feb 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Study: Canadian Open Genetics Repository
Accession: SCV000900936.2 First in ClinVar: May 06, 2019 Last updated: Mar 11, 2023 |
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Likely pathogenic
(Oct 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002018442.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Uncertain significance
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001345836.4
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces alanine with threonine at codon 143 of the GLA protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces alanine with threonine at codon 143 of the GLA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant leads to 36% residual alpha-galactosidase A (GLA) enzyme activity in transfected cells (PMID: 16773563). This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 25040344, 32531501, Koraichi et al. 2021, DOI: 10.1016/j.acvdsp.2020.10.086). However, two of them also carried a pathogenic variant in the MYBPC3 gene, which could fully explain the observed phenotype. This variant has been reported in many individuals with Fabry disease-related symptoms, such as renal failure, angiokeratoma, neuropathic pain, stroke, left ventricular hypertrophy, or other cardiac symptoms (PMID: 16773563, 21549080, 23219219, 27142856 , 30902821, 31650418, 31860127, 31907047, 31949022, 32011328, 32281532, 33617311, 35743707). Some adult male relatives carrying this variant have been reported to be asymptomatic (PMID: 21549080, 25040344, 27142856). Male carriers of this variant usually showed high residual GLA enzyme activity, while plasma globotriaosylsphingosine (lyso-Gb3) levels were typically normal. Both enzymatic activity and lyso-Gb3 levels were normal in most female carriers. Furthermore, cardiac and kidney biopsies from four symptomatic carriers showed no buildup of Gb3 in their affected organs (PMID: 23430526, 25040344). One study evaluating outcomes in cases of newborn screening results for this variant showed that plasma globotriaosylsphingosine (lyso-Gb3) levels were normal in all cases evaluated (PMID: 36156392). This variant has been identified in 104/205433 chromosomes (88/92769 Non-Finnish European chromosomes), including 29 hemizygotes, in the general population by the Genome Aggregation Database (gnomAD). This variant allele frequency in the general population is higher than expected for a disease-causing GLA variant. However, due to the observation in many individuals described as having Fabry disease-related phenotypes and some functional studies showing partially reduced GLA enzyme activity, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503838.2
First in ClinVar: Apr 30, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace alanine with threonine at codon 143 of the GLA protein (p.Ala143Thr). The alanine residue is moderately conserved (100 … (more)
This sequence change is predicted to replace alanine with threonine at codon 143 of the GLA protein (p.Ala143Thr). The alanine residue is moderately conserved (100 vertebrates, UCSC), and is located in a predicted disulphide bond that is not present in a known functional domain. There is a small physicochemical difference between alanine and threonine. The variant is present in a large population cohort at a frequency of 0.05% (rs104894845, 104/205,433 alleles, 0 homozygotes, 29 hemizygotes in gnomAD v2.1.1), including 14 hemizygote males with an age range of 30-75 years in the control cohort (BS2). The variant has been identified in individuals varying from unaffected to classical and variant Fabry disease (PMID: 9100224, 23430526). Male hemizygotes typically demonstrate residual alpha galactosidase activity and normal globotriaosylceramide levels in the blood or tissue (PMID: 23430526, 27142856). In vitro expression studies have consistently shown ~35% of wild-type activity for the variant allele, and localisation of the enzyme to the lysosome (PMID: 16595074, 16773563, 23935525). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms - PP3). Additionally, a variant at the same position with a different missense change (p.Ala143Pro) determined to be pathogenic has been seen before (ClinVar ID: 10769 - PM5). The International Fabry Disease Genotype-Phenotype Database (dbFGP) classifies p.Ala143Thr as likely benign, but recommends clinical evaluation of the patient and at-risk family members to determine the clinical relevance of the variant. Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as a VARIANT of UNCERTAIN SIGNIFICANCE. Following criteria are met: BS2, PM5, PP3. (less)
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Uncertain significance
(Oct 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000740050.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.A143T variant (also known as c.427G>A), located in coding exon 3 of the GLA gene, results from a G to A substitution at nucleotide … (more)
The p.A143T variant (also known as c.427G>A), located in coding exon 3 of the GLA gene, results from a G to A substitution at nucleotide position 427. The alanine at codon 143 is replaced by threonine, an amino acid with similar properties. This variant was first reported in a newborn with decreased alpha-galactosidase A (α-Gal A ) activity (Eng CM et al. Mol. Med., 1997 Mar;3:174-82). This variant was also reported in a male with a single angiokeratoma and in a female control whose son had a previous diagnosis of Fabry disease (Corry A et al. Dermatol. Online J., 2011 Apr;17:5; Gonzalez-Garay ML et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Oct;110:16957-62) It has been suggested that this is a late-onset variant of Fabry disease and has been identified in individuals with involvement of the heart, cerebrovascular, and renal systems (Dobrovolny R et al. J. Mol. Med., 2005 Aug;83:647-54; Spada M et al. Am. J. Hum. Genet., 2006 Jul;79:31-40; Merta M et al. Nephrol. Dial. Transplant., 2007 Jan;22:179-86; Monserrat L et al. J. Am. Coll. Cardiol., 2007 Dec;50:2399-403; Brouns R et al. Stroke, 2010 May;41:863-8; Terryn W et al. Int. J. Cardiol., 2013 Sep;167:2555-60; Varela P et al. Orphanet J Rare Dis, 2020 01;15:30). However, biopsies of affected organs, including nerve, heart, and kidney, in individuals with this variant have shown no evidence of Fabry disease (Terryn W et al. JIMD Rep., 2013 Jul;8:101-8; Sagnelli A et al. Neuromuscul. Disord., 2014 Mar;24:272-6; Smid BE et al. Clin. Genet., 2015 Aug;88:161-6). Males with normal or residual α-Gal A levels have also been reported (De Brabander I et al. Clin Neurol Neurosurg, 2013 Jul;115:1088-93; Smid BE et al. Clin. Genet., 2015 Aug;88:161-6; Lenders M et al. Orphanet J Rare Dis., 2016 May;11(1):54). In addition, functional studies of this alteration have also shown residual enzyme activity (Shabbeer J et al. Hum. Genomics, 2006 Mar;2:297-309; Lukas J et al. PLoS Genet., 2013 Aug;9(8)e1003632). Based on data from gnomAD, the A allele has an overall frequency of approximately 0.05% (104/205433) total alleles studied, including a total of 29 hemizygotes. The highest observed frequency was 0.23% (44/19165) of Swedish alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. (less)
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Likely benign
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001150412.22
First in ClinVar: Feb 03, 2020 Last updated: May 12, 2024 |
Comment:
GLA: BS2; RPL36A-HNRNPH2: BS2
Number of individuals with the variant: 5
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Uncertain significance
(Aug 27, 2015)
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criteria provided, single submitter
Method: clinical testing
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Cardiomyopathy
Variant found in two individuals
(more...)
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000206969.3
First in ClinVar: Feb 06, 2015 Last updated: Feb 27, 2016 |
Number of individuals with the variant: 3
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Pathogenic
(Sep 14, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281136.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
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Uncertain significance
(Sep 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603838.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
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Likely pathogenic
(Apr 10, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000110119.8
First in ClinVar: Jan 17, 2014 Last updated: Jun 08, 2016 |
Number of individuals with the variant: 182
Sex: mixed
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001141979.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Jul 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
(X-linked inheritance)
Affected status: no
Allele origin:
germline
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University of Iowa Renal Genetics Clinic, University of Iowa
Accession: SCV001250668.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
The A143T variant has an allele frequency that is greater than expected for Fabry disease and was identified in a 59-year-old male with no evidence … (more)
The A143T variant has an allele frequency that is greater than expected for Fabry disease and was identified in a 59-year-old male with no evidence of renal disease. Therefore, this variant meets BS1 and BS2 criteria from the ACMG guidelines. (less)
Clinical Features:
Angiokeratoma (present) , Coronary artery atherosclerosis (present)
Age: 50-59 years
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: United States
Testing laboratory: Mount Sinai Genetic Testing Laboratory
Date variant was reported to submitter: 2016-09-20
Testing laboratory interpretation: not provided
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Uncertain significance
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002054817.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Uncertain significance
(Sep 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: yes
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV002059450.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Uncertain significance
(Dec 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580644.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM1, PM5, PM2_SUP, BS2
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Number of individuals with the variant: 1
Sex: male
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Uncertain significance
(Dec 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Fabry disease
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807752.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PM5 moderated, PP3 supporting, BS2 strong
Number of individuals with the variant: 1
Clinical Features:
Recurrent sinusitis (present) , Hypothyroidism (present) , Diabetes mellitus type 1 (present) , Ulcerative colitis (present) , Pancreatitis (present) , Recurrent pneumonia (present)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Uncertain significance
(Jul 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695740.5
First in ClinVar: Dec 26, 2017 Last updated: Aug 26, 2023 |
Comment:
Variant summary: GLA c.427G>A (p.Ala143Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: GLA c.427G>A (p.Ala143Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 183467 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GLA causing Fabry Disease (0.00055 vs 0.005), allowing no conclusion about variant significance. c.427G>A has been reported in the literature in individuals with a wide spectrum of phenotypes ranging from asymptomatic/normal to mild, late-onset, non-classic Fabry manifestations to classic Fabry disease (examples- Blaydon_2001, Nance_2006, Spada_2006, Monserrat_2007, DeSchoenmakere_2008, Stiles_2020). The variant has also been reported in multiple families in which individuals had Fabry-associated phenotypes such as cardiomyopathy and renal failure, however these findings do not provide conclusive data for co-segregation of the variant with disease (e.g. Spada_2006, deBrabander_2012, Hauth_2018, Valtola_2020). Multiple publications report experimental evidence indicating that the variant results in a reduction of alpha-Gal-A enzyme activity compared to wild-type in both patient cells and cells in which the variant was transiently expressed (e.g. Spada_2006, Lukas_2013, Shabbeer_206, Welford_2018, Lender_2016), however the clinical impact of these findings is not clear, as lyso-Gb-3 levels in some patients with the variant have been reported at levels similar to controls (e.g. Lenders_2016, Lukas_2013, de Brabander_2012, Valtola_2020) and patients have been reported with no typical Gb-3 deposits on kidney biopsy (e.g. Terryn_2012). The following publications have been ascertained in the context of this evaluation (PMID: 18154965, 23935525, 16773563, 9100224, 16533976, 23430526, 18596132, 16595074, 23219219, 11668641, 29867742, 29982630, 27142856, 31949022, 32418857). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified with conflicting assessments (likely benign, n=1; uncertain signifiance, n=16; pathogenic/likely pathogenic, n=5). Based on the evidence outlined above, until additional information becomes available, the variant was classified as uncertain significance. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Fabry disease
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV000484907.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
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Pathogenic
(Mar 01, 2006)
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no assertion criteria provided
Method: literature only
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FABRY DISEASE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000031727.2
First in ClinVar: Apr 04, 2013 Last updated: May 29, 2016 |
Comment on evidence:
In a 34-year-old man with Fabry disease (301500), Nance et al. (2006) identified a G-to-A transition in the GLA gene, resulting in an ala143-to-thr (A143T) … (more)
In a 34-year-old man with Fabry disease (301500), Nance et al. (2006) identified a G-to-A transition in the GLA gene, resulting in an ala143-to-thr (A143T) substitution. The patient had a 5-year history of progressive activity-induced leg and foot cramps and fasciculations with pain. No other stigmata of Fabry disease was present. His mother, who also carried the mutation, had a similar phenotype. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Fabry disease
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000607180.1
First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Delayed puberty (present) , Abnormality of the lens (present) , Cardiomyopathy (present) , Hypercholesterolemia (present) , Abnormality of urine homeostasis (present)
Age: 50-59 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2015-05-04
Testing laboratory interpretation: Uncertain significance
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not provided
(-)
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no classification provided
Method: literature only
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Fabry disease
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000494668.2
First in ClinVar: Dec 17, 2016 Last updated: Oct 01, 2022 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Fabry disease
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228517.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Uncertain significance and reported on 09-04-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more)
Variant interpreted as Uncertain significance and reported on 09-04-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Family history (present)
Age: 0-9 years
Sex: male
Method: Single Gene Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2018-09-04
Testing laboratory interpretation: Uncertain significance
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Fabry Disease. | Adam MP | - | 2024 | PMID: 20301469 |
Newborn screening for Fabry disease in Oregon: Approaching the iceberg of A143T and variants of uncertain significance. | Viall S | American journal of medical genetics. Part C, Seminars in medical genetics | 2022 | PMID: 36156392 |
Fabry Disease in Slovakia: How the Situation Has Changed over 20 Years of Treatment. | Jurickova K | Journal of personalized medicine | 2022 | PMID: 35743707 |
Screening for Fabry Disease in Male Patients With Arrhythmia Requiring a Pacemaker or an Implantable Cardioverter-Defibrillator. | Hemelsoet D | Circulation | 2021 | PMID: 33617311 |
Predictors of Fabry disease in patients with hypertrophic cardiomyopathy: How to guide the diagnostic strategy? | Azevedo O | American heart journal | 2020 | PMID: 32531501 |
A comprehensive testing algorithm for the diagnosis of Fabry disease in males and females. | Stiles AR | Molecular genetics and metabolism | 2020 | PMID: 32418857 |
Fabry Disease Screening in Patients With Kidney Transplant: A Single-Center Study in Turkey. | Erdogmus S | Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation | 2020 | PMID: 32281532 |
Ratio of Fabry disease in patients with idiopathic left ventricular hypertrophy: A single-center study in Turkey. | Barman HA | Anatolian journal of cardiology | 2020 | PMID: 32011328 |
Correlation between GLA variants and alpha-Galactosidase A profile in dried blood spot: an observational study in Brazilian patients. | Varela P | Orphanet journal of rare diseases | 2020 | PMID: 31996269 |
Newborn screening for Fabry disease in the western region of Japan. | Sawada T | Molecular genetics and metabolism reports | 2020 | PMID: 31956509 |
Cardiomyopathy associated with the Ala143Thr variant of the α-galactosidase A gene. | Valtola K | Heart (British Cardiac Society) | 2020 | PMID: 31949022 |
Higher rate of rheumatic manifestations and delay in diagnosis in Brazilian Fabry disease patients. | Rosa Neto NS | Advances in rheumatology (London, England) | 2020 | PMID: 31907047 |
Diagnostic strategy for females suspected of Fabry disease. | Balendran S | Clinical genetics | 2020 | PMID: 31860127 |
Identifying Fabry patients in dialysis population: prevalence of GLA mutations by renal clinic screening, 1995-2019. | Capuano I | Journal of nephrology | 2020 | PMID: 31650418 |
Translational readthrough of GLA nonsense mutations suggests dominant-negative effects exerted by the interaction of wild-type and missense variants. | Lombardi S | RNA biology | 2020 | PMID: 31613176 |
Clinical characteristics of patients with alpha-galactosidase A gene variants in a German multicentre cohort of early undifferentiated arthritis. | Vordenbäumen S | Annals of the rheumatic diseases | 2019 | PMID: 30902821 |
Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types. | Welford RWD | Human molecular genetics | 2018 | PMID: 29982630 |
Galactosidase Alpha p.A143T Variant Fabry Disease May Result in a Phenotype With Multifocal Microvascular Cerebral Involvement at a Young Age. | Hauth L | Frontiers in neurology | 2018 | PMID: 29867742 |
The Psychosocial Impact of Carrying a Debated Variant in the GLA Gene. | Macklin S | Journal of genetic counseling | 2018 | PMID: 28799081 |
Screening Fabry's disease in chronic kidney disease patients not on dialysis: a multicenter study. | Yeniçerioğlu Y | Renal failure | 2017 | PMID: 27832731 |
Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant. | Lenders M | Orphanet journal of rare diseases | 2016 | PMID: 27142856 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. | Alfares AA | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25611685 |
Molecular damage in Fabry disease: characterization and prediction of alpha-galactosidase A pathological mutations. | Riera C | Proteins | 2015 | PMID: 25382311 |
Diagnostic dilemmas in Fabry disease: a case series study on GLA mutations of unknown clinical significance. | Smid BE | Clinical genetics | 2015 | PMID: 25040344 |
The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience. | Lawrence L | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24784157 |
Adult polyglucosan body disease in a patient originally diagnosed with Fabry's disease. | Sagnelli A | Neuromuscular disorders : NMD | 2014 | PMID: 24380807 |
Personalized genomic disease risk of volunteers. | Gonzalez-Garay ML | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 24082139 |
Functional characterisation of alpha-galactosidase a mutations as a basis for a new classification system in fabry disease. | Lukas J | PLoS genetics | 2013 | PMID: 23935525 |
Questioning the Pathogenic Role of the GLA p.Ala143Thr "Mutation" in Fabry Disease: Implications for Screening Studies and ERT. | Terryn W | JIMD reports | 2013 | PMID: 23430526 |
Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young. | De Brabander I | Clinical neurology and neurosurgery | 2013 | PMID: 23219219 |
Prevalence of Fabry disease in a predominantly hypertensive population with left ventricular hypertrophy. | Terryn W | International journal of cardiology | 2013 | PMID: 22805550 |
A pharmacogenetic approach to identify mutant forms of α-galactosidase A that respond to a pharmacological chaperone for Fabry disease. | Wu X | Human mutation | 2011 | PMID: 21598360 |
A family with Fabry disease diagnosed by a single angiokeratoma. | Corry A | Dermatology online journal | 2011 | PMID: 21549080 |
Belgian Fabry study: prevalence of Fabry disease in a cohort of 1000 young patients with cerebrovascular disease. | Brouns R | Stroke | 2010 | PMID: 20360539 |
High incidence of the cardiac variant of Fabry disease revealed by newborn screening in the Taiwan Chinese population. | Lin HY | Circulation. Cardiovascular genetics | 2009 | PMID: 20031620 |
Two-tier approach for the detection of alpha-galactosidase A deficiency in kidney transplant recipients. | De Schoenmakere G | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2008 | PMID: 18596132 |
Two-tier approach for the detection of alpha-galactosidase A deficiency in a predominantly female haemodialysis population. | Terryn W | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2008 | PMID: 17804462 |
Prevalence of fabry disease in a cohort of 508 unrelated patients with hypertrophic cardiomyopathy. | Monserrat L | Journal of the American College of Cardiology | 2007 | PMID: 18154965 |
Screening for pharmacological chaperones in Fabry disease. | Shin SH | Biochemical and biophysical research communications | 2007 | PMID: 17532296 |
A nationwide blood spot screening study for Fabry disease in the Czech Republic haemodialysis patient population. | Merta M | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2007 | PMID: 17040996 |
High incidence of later-onset fabry disease revealed by newborn screening. | Spada M | American journal of human genetics | 2006 | PMID: 16773563 |
Fabry disease: identification of 50 novel alpha-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations. | Shabbeer J | Human genomics | 2006 | PMID: 16595074 |
Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome. | Nance CS | Archives of neurology | 2006 | PMID: 16533976 |
Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the alpha-galactosidase A gene in the Czech and Slovak population. | Dobrovolny R | Journal of molecular medicine (Berlin, Germany) | 2005 | PMID: 15806320 |
Fabry disease: 20 novel GLA mutations in 35 families. | Blaydon D | Human mutation | 2001 | PMID: 11668641 |
Fabry disease: thirty-five mutations in the alpha-galactosidase A gene in patients with classic and variant phenotypes. | Eng CM | Molecular medicine (Cambridge, Mass.) | 1997 | PMID: 9100224 |
A carboxy-terminal truncation of human alpha-galactosidase A in a heterozygous female with Fabry disease and modification of the enzymatic activity by the carboxy-terminal domain. Increased, reduced, or absent enzyme activity depending on number of amino acid residues deleted. | Miyamura N | The Journal of clinical investigation | 1996 | PMID: 8878432 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GLA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/9efc57a1-f81d-40cd-a696-cbdcd5cfa3dd | - | - | - | - |
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Text-mined citations for rs104894845 ...
HelpRecord last updated Jun 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.