ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.943C>T (p.Arg315Cys) (rs200476515)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620186 SCV000738209 uncertain significance Cardiovascular phenotype 2017-10-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770231 SCV000901662 uncertain significance Cardiomyopathy 2017-07-24 criteria provided, single submitter clinical testing
Color RCV000770231 SCV000913726 uncertain significance Cardiomyopathy 2018-04-16 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the plakin domain C0 of the DSP protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been observed in an individual with arrhythmogenic right ventricular cardiomyopathy who also carried a truncating variant in the same gene (PMID: 25616645) and an individual with dilated cardiomyopathy who carried a truncating variant in a different gene (PMID: 24503780). This variant has also been identified in 31/276250 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000766874 SCV000233573 uncertain significance not provided 2017-11-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The R315C variant has been reported in multiple individuals in association with ARVC, DCM, or Brugada syndrome (Pugh et al., 2014; Bhonsale et al., 2015; Te Riele et al., 2015; Groeneweg et al., 2015; Zhao et al., 2016; Zhang et al., 2016; Walsh et al., 2017). Additionally, this variant has been observed in multiple individuals referred for cardiomyopathy or arrhythmia genetic testing at GeneDx. However, for the published cases and the cases observed at GeneDx, most individuals harbored additional cardiogenetic variants, including several cases where a pathogenic variant was also identified. Furthermore, the limited segregation data available are not sufficient to clarify the role of R315C in disease. The R315C variant is also observed in 14/18850 (0.07%) alleles from individuals of East Asian ancestry in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Although a different missense variant at the same residue (R315P) has been reported in association with ARVC (Walsh et al., 2017), the clinical significance of this variant also remains to be definitively determined. Finally, the R315C variant is also classified as a variant of uncertain significance in ClinVar by other clinical laboratories (SCV000061787.4, SCV000288555.1; Landrum et al., 2016).
Illumina Clinical Services Laboratory,Illumina RCV000322105 SCV000464870 likely benign Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000355871 SCV000464871 likely benign Skin fragility woolly hair syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000263737 SCV000464872 likely benign Epidermolysis bullosa, lethal acantholytic 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000316563 SCV000464873 likely benign Ectodermal dysplasia skin fragility syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000232142 SCV000288555 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2016-02-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 315 of the DSP protein (p.Arg315Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs200476515, ExAC 0.05%). This variant has been observed in one individual with arrhythmogenic right ventricular dysplasia (PMID: 25616645) and one individual with dilated cardiomyopathy (PMID: 24503780). However, both of these individuals also had different pathogenic variants that would explain their phenotypes, suggesting this c.943C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 44982). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038121 SCV000061787 uncertain significance not specified 2015-04-08 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000038121 SCV000280099 uncertain significance not specified no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below, we classify this as a variant of unknown significance (VUS). Mutations in the DSP gene have been reported in at least 7% of patients with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC). Harvard’s LMM has reported this variant in two patients with dilated cardiomyopathy (DCM) who also carried variants in multiple other cardiomyopathy genes. They classified it as a variant of unknown significance (Pugh et al. 2014, Supplementary Data). This is a non-conservative amino acid change from a positively-charged arginine to a polar, uncharged cysteine capable of forming disulfide bonds. The arginine at codon 315 is not conserved across species (it is an arginine in 6 out of 8 vertebrate species, and a leucine in 2 others). In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. No variants within 10 amino acid residues have been listed in HGMD in association with ARVC (HGMD professional version as of January 17, 2014). The closest is Ser299Arg. In total the variant has been seen in 2 out of ~7500 individuals from population datasets. It was found in 1 Han Chinese individual in 1000 Genomes (1/197 Han Chinese individuals total). It was also seen in 1 Caucasian individual in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of March 27, 2014). The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension.

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