Submissions for variant NM_004415.4(DSP):c.6166G>C (p.Gly2056Arg)

dbSNP: rs780274878

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001179278	SCV001343890	uncertain significance	Cardiomyopathy	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 2056 of the DSP 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). A functional study has shown that this variant causes the protein insoluble in E. coli cells and low expressed in HeLa cells, suggesting the impairment in DSP protein stability (PMID: 35008956). This variant has been reported in homozygous state in an individual affected with arrhythmogenic right ventricular cardiomyopathy with left ventricular involvement (PMID: 20864495). The proband's three children had no cardiac symptoms, who were obligate heterozygous mutation carriers. This variant has been identified in 1/250594 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258160	SCV001435048	uncertain significance	Arrhythmogenic right ventricular dysplasia 8		criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004006555	SCV004814259	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 2056 of the DSP 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). A functional study has shown that this variant causes the protein insoluble in E. coli cells and low expressed in HeLa cells, suggesting the impairment in DSP protein stability (PMID: 35008956). This variant has been reported in homozygous state in an individual affected with arrhythmogenic right ventricular cardiomyopathy with left ventricular involvement (PMID: 20864495). The proband's three children had no cardiac symptoms, who were obligate heterozygous mutation carriers. This variant has been identified in 1/250594 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	RCV004702665	SCV005201566	likely pathogenic	not provided	2023-11-24	criteria provided, single submitter	clinical testing	Published functional studies suggest that this variant compromises plakin repeat domain (PRD) structure of the DSP protein (PMID: 35008956); 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: 31402444, 34400560, 36142674, 29878302, 35008956, 20864495)