VCV000929896.13 - ClinVar

NM_001943.5(DSG2):c.160G>A (p.Ala54Thr)

Germline

Classification

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.

(4)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001943.5(DSG2):c.160G>A (p.Ala54Thr)

Variation ID: 929896 Accession: VCV000929896.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q12.1 18: 31519881 (GRCh38) [ NCBI UCSC ] 18: 29099844 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jul 4, 2020	Apr 20, 2024	Dec 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001943.5:c.160G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001934.2:p.Ala54Thr	missense
NC_000018.10:g.31519881G>A
NC_000018.9:g.29099844G>A
NG_007072.3:g.26640G>A
LRG_397:g.26640G>A
LRG_397t1:c.160G>A

... more HGVS ... less HGVS

Protein change

A54T

Other names

Canonical SPDI

NC_000018.10:31519880:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Links

dbSNP: rs549421694 VarSome

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
Gene	OMIM	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.
DSG2		Some evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1114	1921

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.
not specified	Uncertain significance (1)	criteria provided, single submitter	Mar 15, 2019	RCV001195230.4
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jan 5, 2021	RCV001525624.2
Arrhythmogenic right ventricular cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Dec 1, 2023	RCV004010609.2
Arrhythmogenic right ventricular dysplasia 10	Uncertain significance (1)	criteria provided, single submitter	Aug 31, 2021	RCV001215860.7

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.
Uncertain significance (Mar 15, 2019)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV001365537.1 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: The p.Ala54Thr variant in DSG2 has not been previously reported in individuals with ARVC but has been identified in 0.003% (1/30602) of South Asian chromosomes … (more) The p.Ala54Thr variant in DSG2 has not been previously reported in individuals with ARVC but has been identified in 0.003% (1/30602) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala54Thr variant is uncertain. ACMG/AMP Criteria applied: PM2, BP4. (less) Number of individuals with the variant: 1
Uncertain significance (Jan 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001735795.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Comment: This missense variant replaces alanine with threonine at codon 54 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces alanine with threonine at codon 54 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with cardiovascular disorder, who also carried a pathogenic variant in the KCNQ1 gene that could explain the observed phenotype (Brockman et al. 2020, DOI: 10.1101/2020.09.03.20181073). This variant has been identified in 1/249490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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)
Uncertain significance (Aug 31, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 10 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001387627.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023	Comment: This sequence change replaces alanine with threonine at codon 54 of the DSG2 protein (p.Ala54Thr). The alanine residue is moderately conserved and there is a … (more) This sequence change replaces alanine with threonine at codon 54 of the DSG2 protein (p.Ala54Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs549421694, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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)
Uncertain Significance (Dec 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmogenic right ventricular cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004819418.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Comment: This missense variant replaces alanine with threonine at codon 54 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure … (more) This missense variant replaces alanine with threonine at codon 54 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with cardiovascular disorder, who also carried a pathogenic variant in the KCNQ1 gene that could explain the observed phenotype (Brockman et al. 2020, DOI: 10.1101/2020.09.03.20181073). This variant has been identified in 1/249490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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) Number of individuals with the variant: 1

Comment:

The p.Ala54Thr variant in DSG2 has not been previously reported in individuals with ARVC but has been identified in 0.003% (1/30602) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala54Thr variant is uncertain. ACMG/AMP Criteria applied: PM2, BP4.

Comment:

This missense variant replaces alanine with threonine at codon 54 of the DSG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with cardiovascular disorder, who also carried a pathogenic variant in the KCNQ1 gene that could explain the observed phenotype (Brockman et al. 2020, DOI: 10.1101/2020.09.03.20181073). This variant has been identified in 1/249490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.

Comment:

This sequence change replaces alanine with threonine at codon 54 of the DSG2 protein (p.Ala54Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs549421694, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

Comment:

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.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs549421694 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001943.5(DSG2):c.160G>A (p.Ala54Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs549421694 ...