Submissions for variant NM_024422.6(DSC2):c.607C>T (p.Arg203Cys)

dbSNP: rs142331975

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155026	SCV000204709	uncertain significance	not specified	2015-09-22	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg203Cys variant in DSC2 has been reported in 1 heterozygous Caucasian individual with A RVC (Gehmlich 2011) and in 1 Japanese individual with ARVC who carried 2 additio nal DSC2 variants (Ohno 2013). Testing of relatives of the proband reported by O hno 2013 detected the Arg203Cys variant in 1 of 2 relatives with a possible diag nosis of ARVC. This variant has been previously identified by our laboratory in two homozygous adults of Middle Eastern descent with ARVC and biventricular DCM, one of whom had additional minimal features of recessive ARVC. The variant was absent from large population studies but it should be noted that these did not s urvey a large enough number of Middle Eastern individuals to rule out that it is common in this population. Cell culture studies do suggest that the variant aff ects protein function (Gehmlich 2011) although these types of studies may not ac curately reflect biological function. Computational predictions also support tha t the variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg203Cys variant is unce rtain.
Invitae	RCV001065143	SCV001230086	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 203 of the DSC2 protein (p.Arg203Cys). This variant is present in population databases (rs142331975, gnomAD 0.0009%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 21062920, 23514727, 25825460). ClinVar contains an entry for this variant (Variation ID: 72377). 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 expected to disrupt DSC2 protein function. Experimental studies have shown that this missense change affects DSC2 function (PMID: 21062920). This variant disrupts the p.Arg203 amino acid residue in DSC2. Other variant(s) that disrupt this residue have been observed in individuals with DSC2-related conditions (PMID: 21636032), which suggests that this may be a clinically significant amino acid residue. 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001065143	SCV001367679	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2020-03-17	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3.
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001065143	SCV001984559	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2020-11-15	criteria provided, single submitter	clinical testing