ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.8524C>T (p.Arg2842Cys)

gnomAD frequency: 0.00005  dbSNP: rs144850908
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000467147 SCV000543251 likely benign Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2024-12-23 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001183507 SCV001349256 uncertain significance Cardiomyopathy 2023-12-05 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 2842 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 31983221) and in two individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 31568572). This variant has also been identified in 4/276380 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 RCV002244929 SCV002513229 uncertain significance not provided 2022-04-28 criteria provided, single submitter clinical testing Identified in patients with cardiomyopathy in the published literature (Lopes et al., 2015; Kuhnisch et al., 2019; Mazzarotto et al., 2020); at least one patient also harbored a pathogenic variant in the MYBPC3 gene; 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: 31568572, 31983221, 25351510)
All of Us Research Program, National Institutes of Health RCV004000645 SCV004821526 uncertain significance Arrhythmogenic cardiomyopathy with wooly hair and keratoderma 2024-06-11 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 2842 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 31983221) and in two individuals affected with hypertrophic cardiomyopathy (PMID: 25351510, 31568572). This variant has also been identified in 4/276380 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.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations RCV004577523 SCV005061584 uncertain significance Brugada syndrome 1 2024-06-18 criteria provided, single submitter clinical testing Heterozygous variant NM_004415:c.8524C>T (p.Arg2842Cys) in the DSP gene was found on WES data in female proband (31 y.o., Caucasian) with Drug-induced Brugada pattern on ECG and premature ventricular contraction. Additional rare candidate variant NM_001038:c.1486G>A (p.Val496Met) (Class III of pathogenicity) in the SCNN1A gene was found in this proband. The NM_004415:c.8524C>T (p.Arg2842Cys) variant is in The Genome Aggregation Database (gnomAD) v4.1.0 with total MAF 0.00004411 (Date of access 17-06-2024). Clinvar contains an entry for this variant (Variation ID: 405238). This variant has been reported in 3 studies in patients with variable phenotypes (PMID: 25351510‚ 31568572‚ 31983221). Most in silico predictors are inconclusive in the results (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: PM2.

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