ClinVar Genomic variation as it relates to human health
NM_000359.3(TGM1):c.1552G>A (p.Val518Met)
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.
Uncertain significance(1); Benign(4); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000359.3(TGM1):c.1552G>A (p.Val518Met)
Variation ID: 12496 Accession: VCV000012496.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q12 14: 24255457 (GRCh38) [ NCBI UCSC ] 14: 24724663 (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 Aug 22, 2016 May 12, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000359.3:c.1552G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000350.1:p.Val518Met missense NC_000014.9:g.24255457C>T NC_000014.8:g.24724663C>T NG_007150.1:g.12710G>A P22735:p.Val518Met - Protein change
- V518M
- Other names
- -
- Canonical SPDI
- NC_000014.9:24255456: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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0.00359 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00359
1000 Genomes Project 30x 0.00390
Trans-Omics for Precision Medicine (TOPMed) 0.00953
Exome Aggregation Consortium (ExAC) 0.01040
The Genome Aggregation Database (gnomAD) 0.01146
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
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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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TGM1 | - | - |
GRCh38 GRCh38 GRCh37 |
977 | 1010 |
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 (5) |
criteria provided, conflicting classifications
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May 28, 2019 | RCV000013319.37 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Dec 10, 2021 | RCV000246360.11 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000954979.19 |
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 benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive congenital ichthyosis 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001139424.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive congenital ichthyosis 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001271634.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Benign
(Feb 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: SCV002585463.10
First in ClinVar: Oct 22, 2022 Last updated: May 12, 2024 |
Comment:
TGM1: BP4, BS1, BS2
Number of individuals with the variant: 4
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Likely benign
(-)
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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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PreventionGenetics, part of Exact Sciences
Accession: SCV000303825.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Benign
(Jun 23, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000514897.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Benign
(-)
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criteria provided, single submitter
Method: research
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Autosomal recessive congenital ichthyosis 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001435132.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
Comment:
The p.Val518Met variant in TGM1 has been identified in at least 2 individuals with lamellar ichthyosis (PMID: 9545389), and has been identified in >1% of … (more)
The p.Val518Met variant in TGM1 has been identified in at least 2 individuals with lamellar ichthyosis (PMID: 9545389), and has been identified in >1% of Euroopean (Finnish) chromosomes and 6 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for lamellar ichthyosis. (less)
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Likely benign
(Dec 10, 2021)
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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: SCV002050879.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Benign
(Jan 31, 2024)
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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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Invitae
Accession: SCV001101649.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
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Pathogenic
(Apr 01, 2001)
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no assertion criteria provided
Method: literature only
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ICHTHYOSIS, CONGENITAL, AUTOSOMAL RECESSIVE 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033566.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a female patient with autosomal recessive congenital ichthyosis (ARCI1; 242300), Cserhalmi-Friedman et al. (2001) identified compound heterozygosity for a val518-to-met (V518M) and a ser160-to-cys … (more)
In a female patient with autosomal recessive congenital ichthyosis (ARCI1; 242300), Cserhalmi-Friedman et al. (2001) identified compound heterozygosity for a val518-to-met (V518M) and a ser160-to-cys (S160C; 190195.0019) substitution in the TGM1 gene. The unaffected parents were each heterozygous for one of the mutations, neither of which was found in 50 unrelated controls. On her trunk, the patient had large scales and moderate erythema; immunofluorescence microscopy showed positive staining in the stratum granulosum and stratum coreum that corresponded to a normal level of protein, but in vitro enzyme activity assay revealed that mutant enzyme function was reduced to 30% of wildtype activity. (less)
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Benign
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive congenital ichthyosis type 1
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001459977.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Likely benign
(-)
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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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931531.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953140.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Transglutaminase-1 gene mutations in autosomal recessive congenital ichthyosis: summary of mutations (including 23 novel) and modeling of TGase-1. | Herman ML | Human mutation | 2009 | PMID: 19241467 |
Structural changes in epidermal scale and appendages as indicators of defective TGM1 activity. | Rice RH | Archives of dermatological research | 2005 | PMID: 16133457 |
Transglutaminase 1 gene mutations in Italian patients with autosomal recessive lamellar ichthyosis. | Esposito G | The Journal of investigative dermatology | 2001 | PMID: 11348475 |
Diagnosis of autosomal recessive lamellar ichthyosis with mutations in the TGM1 gene. | Cserhalmi-Friedman PB | The British journal of dermatology | 2001 | PMID: 11298529 |
Genotype/phenotype correlation in autosomal recessive lamellar ichthyosis. | Hennies HC | American journal of human genetics | 1998 | PMID: 9545389 |
Text-mined citations for rs35312232 ...
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.