ClinVar Miner

Submissions for variant NM_001943.5(DSG2):c.2569C>T (p.Pro857Ser) (rs775091459)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000692519 SCV000820346 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 10 2019-10-10 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 857 of the DSG2 protein (p.Pro857Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs775091459, ExAC 0.006%). This variant has not been reported in the literature in individuals with DSG2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Illumina Clinical Services Laboratory,Illumina RCV000692519 SCV001284701 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 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 Health, Inc RCV001525888 SCV001736092 uncertain significance Cardiomyopathy 2020-11-11 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 857 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/246544 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.
GeneDx RCV001568950 SCV001792913 uncertain significance not provided 2020-06-29 no assertion criteria provided 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# 571384; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function

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