ClinVar Genomic variation as it relates to human health
NM_000520.6(HEXA):c.805G>A (p.Gly269Ser)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000520.6(HEXA):c.805G>A (p.Gly269Ser)
Variation ID: 3898 Accession: VCV000003898.63
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q23 15: 72350518 (GRCh38) [ NCBI UCSC ] 15: 72642859 (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 Apr 4, 2013 May 12, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000520.6:c.805G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000511.2:p.Gly269Ser missense NM_001318825.2:c.838G>A NP_001305754.1:p.Gly280Ser missense NR_134869.3:n.847G>A non-coding transcript variant NC_000015.10:g.72350518C>T NC_000015.9:g.72642859C>T NG_009017.2:g.30662G>A - Protein change
- G269S, G280S
- Other names
- G805A
- Canonical SPDI
- NC_000015.10:72350517:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
Exome Aggregation Consortium (ExAC) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00013
Trans-Omics for Precision Medicine (TOPMed) 0.00014
The Genome Aggregation Database (gnomAD) 0.00015
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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HEXA | - | - |
GRCh38 GRCh37 |
1127 | 1161 |
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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Pathogenic (1) |
no assertion criteria provided
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Aug 1, 2008 | RCV000004104.7 | |
Pathogenic/Likely pathogenic (13) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000168285.30 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2024 | RCV000434025.27 | |
Gm2-gangliosidosis, late onset
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Pathogenic (1) |
no assertion criteria provided
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Dec 1, 1992 | RCV001810397.4 |
Pathogenic (1) |
criteria provided, single submitter
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Apr 14, 2017 | RCV002408450.5 | |
HEXA-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV003924800.1 |
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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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894058.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Oct 18, 2019)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001194013.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 04, 2020 |
Comment:
NM_000520.4(HEXA):c.805G>A(G269S) is classified as pathogenic in the context of hexosaminidase A deficiency and is associated with the adult-onset form of disease. Sources cited for classification … (more)
NM_000520.4(HEXA):c.805G>A(G269S) is classified as pathogenic in the context of hexosaminidase A deficiency and is associated with the adult-onset form of disease. Sources cited for classification include the following: PMID 15714079, 22006919, 10852376, 8343225, 19815695, 8328462, 2278539, 2522660, and 2522679. Classification of NM_000520.4(HEXA):c.805G>A(G269S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001448072.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Dysarthria (present) , Progressive cerebellar ataxia (present) , Dysphagia (present)
Sex: female
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Pathogenic
(May 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001530446.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 2522679, 21228398, 27682588, … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 2522679, 21228398, 27682588, 22975760, 18490185, 22006919] (less)
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Pathogenic
(Nov 26, 2019)
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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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GeneDx
Accession: SCV000513236.3
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Common pathogenic variant in the Ashkenazi Jewish population and associated with adult-onset Tay-Sachs disease (Kaback et al., 2011); Functional analysis of G269S indicate that it … (more)
Common pathogenic variant in the Ashkenazi Jewish population and associated with adult-onset Tay-Sachs disease (Kaback et al., 2011); Functional analysis of G269S indicate that it forms a defective alpha-subunit which fails to associate with the beta-subunit thus resulting in significantly reduced beta-hexosaminidase activity (Paw et al., 1989; Navon et al., 1989; Ohno et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27033294, 21228398, 27351546, 2522679, 18490185, 22975760, 2522660, 31076878, 22006919, 27682588, 2278539) (less)
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Pathogenic
(Jul 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579018.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM3_STR, PS4_MOD, PM5, PS3_SUP, PM2_SUP, PP3
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Number of individuals with the variant: 4
Sex: male
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767808.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Tay-Sachs disease (MIM#272800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 42 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. Although this variant is located within the splice region and the nucleotide is highly conserved, in silico programs do not predict abberant splicing. (SP) 0600 - Variant is located in the annotated glycosyl hydrolase family 20, catalytic domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic in ClinVar and in many individuals with the adult form of Tay-Sachs disease (PMIDs: 31076878, 27033294). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Oct 16, 2019)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center
Accession: SCV004037345.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
Comment:
The c.805G>A (p.Gly269Ser) variant in HEXA substitutes a conserved glycine residue to a serine at amino acid position 269. This variant localizes to coding exon … (more)
The c.805G>A (p.Gly269Ser) variant in HEXA substitutes a conserved glycine residue to a serine at amino acid position 269. This variant localizes to coding exon 7 of the HEXA gene (14 coding exons in total; NM_000520.6). Functional studies showed decreased enzyme levels due to destabilization of the a-subunit at physiological temperatures affecting the alpha-beta dimerization (PMID: 8328462, 2522660, 2522679, 27682588). Protein modeling have shown that the mutation does not affect the active site which allows for some functionality, allowing for the later onset phenotype (PMID: 18490185). This variant is present in the Genome Aggregation Database (gnomAD) at an allele frequency of 42/282842 (no homozygotes), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in multiple late-onset patients as homozygous or compound heterozygous with another pathogenic variant (PMID: 2278539, 31076878 & 2522679), and is reported in ClinVar as pathogenic (Variation ID: 3898). Missense variants causing different amino acid substitution at the same position have also been reported as pathogenic (PMID: 27896118). (less)
Clinical Features:
Progressive proximal muscle weakness (present) , Weakness of facial musculature (present) , Gait disturbance (present) , Dysarthria (present) , Gastrointestinal dysmotility (present) , Cachexia (present) … (more)
Progressive proximal muscle weakness (present) , Weakness of facial musculature (present) , Gait disturbance (present) , Dysarthria (present) , Gastrointestinal dysmotility (present) , Cachexia (present) , Sensory neuropathy (present) (less)
Age: 50-59 years
Sex: male
Tissue: peripheral blood
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Pathogenic
(Jun 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024983.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000218959.8
First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 269 of the HEXA protein (p.Gly269Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 269 of the HEXA protein (p.Gly269Ser). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121907954, gnomAD 0.07%). This missense change has been observed in individuals with Tay-Sachs disease, also known as adult GM2-gangliosidosis (PMID: 2522679). ClinVar contains an entry for this variant (Variation ID: 3898). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HEXA function (PMID: 2522679, 20363167). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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HEXA-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004739342.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The HEXA c.805G>A variant is predicted to result in the amino acid substitution p.Gly269Ser. This variant has been documented to be causative for infantile and … (more)
The HEXA c.805G>A variant is predicted to result in the amino acid substitution p.Gly269Ser. This variant has been documented to be causative for infantile and adult onset Tay-Sachs disease (Navon et al. 1989. PubMed ID: 2522679; Ohno et al. 2008. PubMed ID: 18490185; Deik and Saunders-Pullman. 2014. PubMed ID: 24327357; Steiner et al. 2016. PubMed ID: 27033294). Taken together, we interpret this variant as pathogenic. (less)
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Pathogenic
(Jan 01, 2024)
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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: SCV001249188.19
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Comment:
HEXA: PM3:Very Strong, PM1, PM5, PM2:Supporting, PS3:Supporting
Number of individuals with the variant: 7
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Pathogenic
(Mar 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697175.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The HEXA c.805G>A (p.Gly269Ser) variant involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome. A functional … (more)
Variant summary: The HEXA c.805G>A (p.Gly269Ser) variant involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome. A functional study, Brown_1993, further supports these predictions. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency 12/121408 (1/10121), which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant of 1/715. Multiple publications have cited the variant in affected homozygote and compound heterozygote individuals, predominantly in Late-Onset TSD. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Aug 31, 2017)
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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: SCV000232069.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 6
Sex: mixed
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Likely pathogenic
(Aug 29, 2019)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369403.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3.
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Pathogenic
(Aug 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764731.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Dystonic disorder (present) , Cognitive impairment (present) , Cerebellar ataxia (present)
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Pathogenic
(Mar 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Accession: SCV004032468.1
First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
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Pathogenic
(Apr 14, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002675688.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.805G>A pathogenic mutation (also known as p.G269S), located in coding exon 7 of the HEXA gene, results from a G to A substitution at … (more)
The c.805G>A pathogenic mutation (also known as p.G269S), located in coding exon 7 of the HEXA gene, results from a G to A substitution at nucleotide position 805. This change occurs in the last base pair of coding exon 7, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the glycine at codon 269 to serine, an amino acid with similar properties. This mutation was first reported in eight adults with Tay-Sachs disease from five unrelated families who were compound heterozygous for this alteration and an infantile-onset mutation (Navon R et al. Science, 1989 Mar;243:1471-4). In another study, this mutation was detected in three homozygous adults with Tay-Sachs disease; family studies confirmed biparental inheritance in one of these individuals (Navon R et al. Am. J. Hum. Genet., 1990 Apr;46:817-21). Although this mutation was predicted to have small impact on the protein structure, extracts from cells expressing G269S showed markedly reduced hexosaminidase activity (Navon R et al. Science, 1989 Mar;243:1471-4; Ohno K et al. Mol. Genet. Metab., 2008 Aug;94:462-8). Based on the available evidence, c.805G>A is classified as a pathogenic mutation. (less)
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Pathogenic
(Dec 01, 1992)
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no assertion criteria provided
Method: literature only
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GM2-GANGLIOSIDOSIS, LATE ONSET
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024310.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013
Comment:
In January, 2022, NCBI staff corrected an error in the representation of 606869.0052, which describes the G to A substitution in the last nucleotide of … (more)
In January, 2022, NCBI staff corrected an error in the representation of 606869.0052, which describes the G to A substitution in the last nucleotide of what is annotated as exon 7 in RefSeqGene NG_009017.2. This SCV previously reported the adjacent intronic allele. (less)
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Comment on evidence:
Hechtman et al. (1992) made reference to a HEXA mutation involving the last nucleotide in exon 7 which resulted in a gly805-to-ala substitution and the … (more)
Hechtman et al. (1992) made reference to a HEXA mutation involving the last nucleotide in exon 7 which resulted in a gly805-to-ala substitution and the clinical picture of adult-onset GM2-gangliosidosis (272800). The mutation is immediately adjacent to the IVS7DS +1 mutation (606869.0051). Both mutations result in the loss of a cleavage site for the restriction endonuclease EcoRII; the 2 mutations can be unequivocally distinguished, however, using allele-specific oligonucleotide hybridization. (less)
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Pathogenic
(Aug 01, 2008)
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no assertion criteria provided
Method: literature only
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GM2-GANGLIOSIDOSIS, ADULT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024270.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 31, 2021 |
Comment on evidence:
In 8 Ashkenazi adult GM2-gangliosidosis (272800) patients from 5 different families, Navon and Proia (1989) found a gly269-to-ser (G269S) substitution. This amino acid substitution was … (more)
In 8 Ashkenazi adult GM2-gangliosidosis (272800) patients from 5 different families, Navon and Proia (1989) found a gly269-to-ser (G269S) substitution. This amino acid substitution was shown to depress drastically the catalytic activity of the alpha chain after expression in COS-1 cells. All the patients proved to be compound heterozygotes of the allele with the gly-to-ser change and 1 of the 2 Ashkenazi infantile Tay-Sachs alleles. Paw et al. (1989) described the molecular basis of adult onset and chronic GM2 gangliosidoses in Ashkenazi Jewish patients known to have a defective association between the alpha and beta subunits of hexosaminidase. They identified a G-to-A substitution at the 3-prime end of exon 7, resulting in the substitution of serine for glycine at position 269 of the alpha subunit. One patient with the adult-onset disorder had inherited this gly-to-ser mutation at position 269 from his father and a null allele from his mother. The same combination of alleles was found in fetal fibroblasts from an association-defective phenotype and in cells from 5 patients with chronic Gm2-gangliosidoses. Navon et al. (1990) found the same gly269-to-ser mutation in 6 adult GM2-gangliosidosis patients from 4 different non-Jewish families. Three of these patients, 2 of whom were brothers, showed a hybridization pattern consistent with homozygosity for the mutation. The others were compound heterozygotes of the gly269-to-ser mutation together with an unidentified alpha-subunit mutation. Navon et al. (1990) suggested that the gly269-to-ser mutation in the Ashkenazi and non-Jewish patients might have had a common origin since the ancestry of the Ashkenazim could be traced to eastern Europe. Kappler et al. (1990) suggested caution in concluding that homozygosity for the gly269-to-ser allele as reported by Navon et al. (1990) is responsible for adult GM2-gangliosidosis. They suggested that it might be a pseudodeficiency with coincidental association with neurologic disease. Proia et al. (1990) provided information suggesting that the mutation is indeed causative. Because hexosaminidase A is heterodimeric, analysis of alpha-chain mutations is not straightforward. Brown and Mahuran (1993) used the techniques of in vitro mutagenesis and transient expression in COS cells to demonstrate that the G269S mutation does not directly affect alpha-dimerization but exerts an indirect effect on the dimer through destabilizing the folded alpha subunit at physiologic temperatures. Two other alpha mutations associated with more severe phenotypes, gly250-to-asp (606869.0013) and glu482-to-lys (606869.0004), appeared to inhibit the initial folding of the subunit. Using structural modeling, Ohno et al. (2008) demonstrated that the gly269 residue is located on the surface of the folded enzyme protein and the G269S mutation only influences a small number of atoms, which correlated with a less severe phenotype and residual enzyme activity. (less)
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Pathogenic
(May 09, 2022)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV003839577.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
DNA sequence analysis of the HEXA gene demonstrated a sequence change, c.805G>A, in exon 7 that results in an amino acid change, p.Gly269Ser. The p.Gly269Ser … (more)
DNA sequence analysis of the HEXA gene demonstrated a sequence change, c.805G>A, in exon 7 that results in an amino acid change, p.Gly269Ser. The p.Gly269Ser change affects a highly conserved amino acid residue located in a domain of the HEXA protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly269Ser substitution. This pathogenic sequence change has previously been described in individuals with HEXA-related disorders and is the most common variant associated with late-onset Tay-Sachs disease (PMID: 27682588, 8328462, 15714079). This sequence change has been described in the gnomAD database with a frequency of 0.068% in the Ashkenazi Jewish subpopulation (dbSNP rs121907954). These collective evidences indicate that this sequence change is pathogenic. Bi-allelic pathogenic variants in the HEXA gene are associated with GM2-gangliosidosis or Tay-Sachs disease (OMIM# 272800), which is a progressive neurodegenerative disorder. (less)
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Pathogenic
(Mar 17, 2017)
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no assertion criteria provided
Method: clinical testing
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Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002086284.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Amyotrophy, cerebellar impairment and psychiatric disease are the main symptoms in a cohort of 14 Czech patients with the late-onset form of Tay-Sachs disease. | Jahnová H | Journal of neurology | 2019 | PMID: 31076878 |
Tay-Sachs disease mutations in HEXA target the α chain of hexosaminidase A to endoplasmic reticulum-associated degradation. | Dersh D | Molecular biology of the cell | 2016 | PMID: 27682588 |
Cerebellar atrophy and muscle weakness: late-onset Tay-Sachs disease outside Jewish populations. | Steiner KM | BMJ case reports | 2016 | PMID: 27033294 |
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
Inhibition of endoplasmic reticulum-associated degradation rescues native folding in loss of function protein misfolding diseases. | Wang F | The Journal of biological chemistry | 2011 | PMID: 22006919 |
Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
Two novel exonic point mutations in HEXA identified in a juvenile Tay-Sachs patient: role of alternative splicing and nonsense-mediated mRNA decay. | Levit A | Molecular genetics and metabolism | 2010 | PMID: 20363167 |
Development of genomic DNA reference materials for genetic testing of disorders common in people of ashkenazi jewish descent. | Kalman L | The Journal of molecular diagnostics : JMD | 2009 | PMID: 19815695 |
Structural consequences of amino acid substitutions causing Tay-Sachs disease. | Ohno K | Molecular genetics and metabolism | 2008 | PMID: 18490185 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Late-onset Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients. | Neudorfer O | Genetics in medicine : official journal of the American College of Medical Genetics | 2005 | PMID: 15714079 |
A novel mutation in the HEXA gene specific to Tay-Sachs disease carriers of Jewish Iraqi origin. | Karpati M | Clinical genetics | 2000 | PMID: 10852376 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Comparison of enzyme and DNA analysis in a Tay-Sachs disease carrier screening program. | Yoo HW | Journal of Korean medical science | 1993 | PMID: 8343225 |
beta-Hexosaminidase isozymes from cells cotransfected with alpha and beta cDNA constructs: analysis of the alpha-subunit missense mutation associated with the adult form of Tay-Sachs disease. | Brown CA | American journal of human genetics | 1993 | PMID: 8328462 |
The intron 7 donor splice site transition: a second Tay-Sachs disease mutation in French Canada. | Hechtman P | Human genetics | 1992 | PMID: 1483696 |
Ashkenazi-Jewish and non-Jewish adult GM2 gangliosidosis patients share a common genetic defect. | Navon R | American journal of human genetics | 1990 | PMID: 2278539 |
Hexosaminidase--pseudodeficiency? | Kappler J | American journal of human genetics | 1990 | PMID: 2145759 |
The mutations in Ashkenazi Jews with adult GM2 gangliosidosis, the adult form of Tay-Sachs disease. | Navon R | Science (New York, N.Y.) | 1989 | PMID: 2522679 |
Molecular basis of adult-onset and chronic GM2 gangliosidoses in patients of Ashkenazi Jewish origin: substitution of serine for glycine at position 269 of the alpha-subunit of beta-hexosaminidase. | Paw BH | Proceedings of the National Academy of Sciences of the United States of America | 1989 | PMID: 2522660 |
Faulty association of alpha- and beta-subunits in some forms of beta-hexosaminidase A deficiency. | d'Azzo A | The Journal of biological chemistry | 1984 | PMID: 6236221 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HEXA | - | - | - | - |
https://www.ncbi.nlm.nih.gov/books/NBK1218/ | - | - | - | - |
Proia, R. L., Kolodny, E. H., Navon, R. Reply to Kappler et al. (Letter) Am. J. Hum. Genet. 47: 881-882, 1990. | - | - | - | - |
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Text-mined citations for rs121907954 ...
HelpRecord last updated May 12, 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.