Submissions for variant NM_004415.4(DSP):c.1352G>A (p.Arg451His)

dbSNP: rs786204294

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230398	SCV000288526	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 451 of the DSP protein (p.Arg451His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257, 33460606; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188459). 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.Arg451 amino acid residue in DSP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31194698). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001582663	SCV001820532	likely pathogenic	not provided	2024-11-20	criteria provided, single submitter	clinical testing	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: 34352074, 31402444, 33460606, 36175056, 27532257)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150035	SCV003838421	uncertain significance	Cardiomyopathy	2022-02-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995634	SCV004829919	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-11-30	criteria provided, single submitter	clinical testing