Submissions for variant NM_001943.5(DSG2):c.1795T>C (p.Cys599Arg)

dbSNP: rs762413624

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181223	SCV000233502	uncertain significance	not provided	2014-04-22	criteria provided, single submitter	clinical testing	p.Cys599Arg (TGC>CGC): c.1795 T>C in exon 12 of the DSG2 gene (NM_001943.3). The C599R variant has not been published as a mutation or as a benign polymorphism to our knowledge. The C599R variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C599R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. No missense mutations in nearby residues have been reported in association with ARVC.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170376	SCV001332950	uncertain significance	Cardiomyopathy	2019-03-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170376	SCV001344286	uncertain significance	Cardiomyopathy	2021-03-26	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with arginine at codon 599 of the DSG2 protein. Computational prediction suggests that this variant may have 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/249172 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.
Invitae	RCV001852262	SCV002204599	uncertain significance	Arrhythmogenic right ventricular dysplasia 10	2023-04-25	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs762413624, gnomAD 0.0009%). 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: 199811). This variant has not been reported in the literature in individuals affected with DSG2-related conditions. This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 599 of the DSG2 protein (p.Cys599Arg).