ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.1562A>G (p.Asp521Gly)

gnomAD frequency: 0.00001  dbSNP: rs730880077
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000539173 SCV000641964 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2023-03-07 criteria provided, single submitter clinical testing 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 protein function. ClinVar contains an entry for this variant (Variation ID: 180320). This missense change has been observed in individual(s) with DSG2-related conditions (PMID: 29178656). This variant is present in population databases (rs730880077, gnomAD 0.02%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 521 of the DSG2 protein (p.Asp521Gly).
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute RCV000157185 SCV001156268 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2017-03-16 criteria provided, single submitter research The DSG2 Asp521Gly is absent in the 1000 genomes project (http://www.1000genomes.org/), and present at low frequency in the Exome Aggregation Consortium dataset (MAF=0.000025; http://exac.broadinstitute.org/). We identified this variant in a HCM patient with no family history of disease or SCD. Computational tools SIFT, MutationTaster, and PolyPhen-2 predict the variant to have a deleterious effect. In summary, while this is a rare variant, there is currently no evidence that DSG2 can cause an HCM phenotype, therefore we classify DSG2 Asp521Gly as a variant of "uncertain significance".
Illumina Laboratory Services, Illumina RCV000539173 SCV001286953 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health RCV001181773 SCV001346995 uncertain significance Cardiomyopathy 2023-04-03 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glycine at codon 521 of the DSG2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy or dysplasia (PMID: 29178656). This variant has been identified in 5/249444 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.
All of Us Research Program, National Institutes of Health RCV000157185 SCV004819562 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2023-06-26 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glycine at codon 521 of the DSG2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with arrhythmogenic right ventricular cardiomyopathy or dysplasia (PMID: 29178656). This variant has been identified in 5/249444 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.
Ambry Genetics RCV004019894 SCV005018364 uncertain significance Cardiovascular phenotype 2023-11-15 criteria provided, single submitter clinical testing The p.D521G variant (also known as c.1562A>G), located in coding exon 11 of the DSG2 gene, results from an A to G substitution at nucleotide position 1562. The aspartic acid at codon 521 is replaced by glycine, an amino acid with similar properties. This variant co-occurred with other DSG2 variants in individuals from an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort (Wada Y et al. Mol Genet Genomic Med, 2017 Nov;5:639-651). This variant was also detected in a sudden death case with features of ARVC (Takahashi Y et al. Int J Legal Med, 2023 Nov;137:1927-1937). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Blueprint Genetics RCV000157185 SCV000206909 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2014-10-14 no assertion criteria provided clinical testing

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