ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.478C>T (p.Arg160Ter) (rs397516943)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038058 SCV000061724 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2016-10-17 criteria provided, single submitter clinical testing The p.Arg160X variant in DSP has been reported in 1 heterozygote with ARVC and 2 heterozygotes with ARVC/DCM, woolly hair, and palmoplantar keratoderma (Te Riel e 2013, LMM Data). It segregated with arrhythmia in one relative, and with wooll y hair and palmoplantar keratoderma in another relative from the same family. It was absent from large population studies. This nonsense variant leads to a prem ature termination codon at position 160, which is predicted to lead to a truncat ed or absent protein. Frameshift and nonsense variants in DSP have been reported in patients with ARVC (, but recent evidence supports that they can also cause DCM (Pugh 2014). When inherited in a recessive manner, multiple variants in DSP can result in ARVC or DCM with woolly hair and keratod erma or other skin findings (Norgett 2000, Alcalai 2003). In summary, although a dditional studies are required to fully establish its clinical significance, the p.Arg160X variant is likely pathogenic.
GeneDx RCV000181275 SCV000233564 pathogenic not provided 2018-07-24 criteria provided, single submitter clinical testing The R160X pathogenic variant in the DSP gene has been reported in association with ARVC and DCM; however, detailed clinical and segregation information was not provided (te Riele et al., 2013; Walsh et al., 2017). The R160X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the DSP gene have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). Furthermore, the R160X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000472617 SCV000543223 pathogenic Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-12-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 160 (p.Arg160*) of the DSP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSP are known to be pathogenic. This particular variant has been reported in the literature in an individual with arrhythmogenic right ventricular cardiomyopathy (PMID: 23810894). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000621394 SCV000736189 pathogenic Cardiovascular phenotype 2018-01-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000181275 SCV000924778 pathogenic not provided 2016-12-09 no assertion criteria provided provider interpretation Given that it is a nonsense variant in a gene where loss of function is a known mechanisms of disease, absence in control populations and moderate case data, we consider this variant likely disease causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 2 unrelated case of arrhythmogenic right ventricular cardiomyopathy (ARVC) (not including this patient's family). The number of cases may be more, but it is difficult to discern because the patient reported below may have had testing at either GeneDx or LMM, and may be redundant with the ClinVar entries. This variant has an entry in ClinVar. GeneDx asserts that it is pathogenic and LMM asserts that it is likely pathogenic. te Riele et al 2013 report this variant in a study reporting on value of cardiac MRI in risk stratification for patients with ARVC. The patients were recruited from the Johns Hopkins ARVC registry. They were eligible for the study if they had a pathogenic desmosomal variant and had no history of sustained VT or VF. No other specific phenotypic information was given. The majority of the mutations in the DSP gene associated with ARVC in HGMD are nonsense or frameshifts mutations (Stenson P et al., 2009). Furthermore, in the ExAC constraint analyses indicates DSP is intolerant to loss of function/truncating variation (pLI - 1.000). This variant is not listed in the Genome Aggregation Consortium Dataset (gnomAD;, which currently includes variant calls on >126,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 90x. It is also absent in the ExAC database.

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