Submissions for variant NM_004415.4(DSP):c.7096C>T (p.Arg2366Cys)

dbSNP: rs28931610

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000610244	SCV000710898	uncertain significance	not specified	2016-06-16	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg2366Cy s variant in DSP has been reported in the compound heterozygous state in 1 indiv idual with clinical features of Naxos disease (skin fragility and woolly hair sy ndrome; Whittock 2002), but has not been identified in large population studies. A different amino acid change (p.Arg2366His) at the same codon has been reporte d in the homozygous state in 1 individual with clinical features of Naxos diseas e and segregated with disease in 4 affected family members (Al-Owain 2011). Howe ver, neither family presented with a cardiac phenotype. Computational prediction tools and conservation analysis suggest that the p.Arg2366Cys variant may impac t the protein, though this information is not predictive enough to determine pat hogenicity. When inherited in a recessive manner, variants in DSP can result in ARVC or DCM with woolly hair and keratoderma or other skin findings (Norgett 200 0, Alcalai 2003). In summary, while there is some suspicion for a pathogenic rol e, the clinical significance of the p.Arg2366Cys variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851908	SCV002137315	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-04-23	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 2366 of the DSP protein (p.Arg2366Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal recessive Carvajal syndrome (PMID: 11841538, 30133754). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 16841). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg2366 amino acid residue in DSP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20738328). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV004700249	SCV005201568	likely pathogenic	not provided	2024-01-16	criteria provided, single submitter	clinical testing	Published functional studies suggest this variant results in impairment of ligand binding, however additional studies are needed to validate the functional effect of this variant (PMID: 30354334); Not observed at significant frequency in large population cohorts (gnomAD); 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: 35008956, 11841538, 21981446, 30133754, 30354334)
OMIM	RCV003233072	SCV000038614	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2002-02-01	no assertion criteria provided	literature only