Submissions for variant NM_024422.6(DSC2):c.14G>T (p.Arg5Leu)

gnomAD frequency: 0.00001  dbSNP: rs899009158

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001126682	SCV001285909	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2017-04-28	criteria provided, single submitter	clinical testing	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001176570	SCV001340593	uncertain significance	Cardiomyopathy	2023-08-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 5 of the DSC2 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 1/120154 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	RCV002393362	SCV002700551	uncertain significance	Cardiovascular phenotype	2022-08-14	criteria provided, single submitter	clinical testing	The p.R5L variant (also known as c.14G>T), located in coding exon 1 of the DSC2 gene, results from a G to T substitution at nucleotide position 14. The arginine at codon 5 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. 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.
Fulgent Genetics, Fulgent Genetics	RCV001126682	SCV002815775	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-02-17	criteria provided, single submitter	clinical testing
Invitae	RCV001126682	SCV003456864	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-03-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 5 of the DSC2 protein (p.Arg5Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 891405). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
All of Us Research Program, National Institutes of Health	RCV004000252	SCV004819396	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 5 of the DSC2 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 1/120154 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.
Clinical Genomics Program, Stanford Medicine	RCV001126682	SCV005045530	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2021-07-21	criteria provided, single submitter	clinical testing	The p.Arg5Leu variant in the DSC2gene has not been previously reported in association with disease. This variant has been identified in 1/21,118 South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that this variant does not impact protein function; however, the accuracy of in silicoalgorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Arg5Leu variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; BP4]