Submissions for variant NM_024422.6(DSC2):c.2393G>T (p.Arg798Leu)

dbSNP: rs61731921

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039422	SCV000063106	uncertain significance	not specified	2013-01-11	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Arg798Leu varia nt in DSC2 has not been reported in the literature nor previously identified by our laboratory. This variant has also not been identified in large and broad Eur opean American and African American populations by the NHLBI Exome Sequencing Pr oject (http://evs.gs.washington.edu/EVS). However, we cannot exclude that it may be common in other populations. Arginine (Arg) at position 798 is not conserved in evolution, suggesting that a change may be tolerated. Computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not prov ide strong support for or against an impact to the protein. Although this data s upports that the Arg798Leu variant may be benign, additional studies are needed to fully assess its clinical significance.
Invitae	RCV000226818	SCV000290731	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-10-18	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 798 of the DSC2 protein (p.Arg798Leu). This variant is present in population databases (rs61731921, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of DSC2-related conditions (PMID: 31534214, 31983221). ClinVar contains an entry for this variant (Variation ID: 46179). 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 DSC2 protein function. 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	RCV001178863	SCV001343416	uncertain significance	Cardiomyopathy	2022-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 798 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 been reported in an individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has aslo been identified in 11/282524 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	RCV001659978	SCV001875197	uncertain significance	not provided	2023-01-26	criteria provided, single submitter	clinical testing	Identified in association with sudden cardiac death and dilated cardiomyopathy (Lahrouchi et al, 2020; Mazzarotto et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31534214, 31983221)
Fulgent Genetics, Fulgent Genetics	RCV000226818	SCV002775420	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2022-02-23	criteria provided, single submitter	clinical testing