ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.862G>A (p.Val288Ile)

gnomAD frequency: 0.00005  dbSNP: rs780374242
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181247 SCV000233526 uncertain significance not provided 2020-04-13 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 199829; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 32880476)
Ambry Genetics RCV000241983 SCV000318697 uncertain significance Cardiovascular phenotype 2021-09-15 criteria provided, single submitter clinical testing The p.V288I variant (also known as c.862G>A), located in coding exon 8 of the DSG2 gene, results from a G to A substitution at nucleotide position 862. The valine at codon 288 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been detected in individuals from cohorts with unknown and dilated cardiomyopathy; however, details were limited (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487). This variant has also been detected in a pediatric exome cohort in individuals not known to have arrhythmogenic right ventricular cardiomyopathy (Headrick AT et al. Mol Genet Genomic Med, 2019 06;7:e593). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000794604 SCV000934023 uncertain significance Arrhythmogenic right ventricular dysplasia 10 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 288 of the DSG2 protein (p.Val288Ile). This variant is present in population databases (rs780374242, gnomAD 0.009%). This missense change has been observed in individual(s) with cardiomyopathy and/or dilated cardiomyopathy (PMID: 30847666, 32880476). ClinVar contains an entry for this variant (Variation ID: 199829). 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 DSG2 protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health RCV001180302 SCV001345197 uncertain significance Cardiomyopathy 2023-11-29 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 288 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 dilated cardiomyopathy or an unspecified cardiomyopathy (PMID: 30847666, 32880476, 37477868). This variant has been identified in 12/249358 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001201211 SCV001372294 likely benign not specified 2020-06-10 criteria provided, single submitter clinical testing Variant summary: DSG2 c.862G>A (p.Val288Ile) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 249358 control chromosomes, predominantly at a frequency of 8.8e-05 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, c.862G>A has not been reported in the literature in individuals affected with Arrhythmia and no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics, Academic Medical Center RCV000181247 SCV001922280 uncertain significance not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000181247 SCV001954916 uncertain significance not provided no assertion criteria provided clinical testing

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