ClinVar Miner

Submissions for variant NM_024422.6(DSC2):c.2587G>A (p.Gly863Arg) (rs147109895)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756035 SCV000883740 uncertain significance not provided 2017-08-14 criteria provided, single submitter clinical testing The c.2587G>A; p.Gly863Arg variant (rs147109895) was observed in both patient and control individuals assessed for dilated cardiomyopathy (Elliott, 2010). In addition the p.Gly863Arg variant was reported in one patient analyzed for arrhythmogenic right ventricular dysplasia/cardiomyopathy, whom also carried a frameshift PKP2 allele associated with this disease (Cox, 2011). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.06 percent in the South Asian population (identified on 19 out of 30,770 chromosomes), and is listed in the ClinVar database with uncertain significance (Variation ID: 46183). The glycine at position 863 is highly conserved and computational analyses of the p.Gly863Arg variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Gly863Arg variant with certainty.
Ambry Genetics RCV000246287 SCV000320415 uncertain significance Cardiovascular phenotype 2016-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000039426 SCV000804865 uncertain significance not specified 2016-09-23 no assertion criteria provided clinical testing
Color RCV000776155 SCV000911158 uncertain significance Cardiomyopathy 2018-07-15 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the intracellular cadherin segment of the DSC2 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 reported in an individual with dilated cardiomyopathy, as well as in an unaffected control subject (PMID: 20716751). This variant has also been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy, who also carried a pathogenic variant in the PKP2 gene (PMID: 21606396). This variant has been identified in 73/276846 chromosomes (0.0263%) in the general population by the Genome Aggregation Database (gnomAD). Although the relatively high frequency of this variant in the general population suggests that it is unlikely to be disease-causing, available evidence is insufficient to rule out the pathogenicity of this variant conclusively.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000227283 SCV000536730 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2015-07-30 no assertion criteria provided research
GeneDx RCV000756035 SCV000233445 uncertain significance not provided 2018-12-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSC2 gene. The G863R variant has been previously reported in at least three individuals in association with ARVC (Cox et al., 2011; Kapplinger et al., 2011; Bhonsale et al. 2013; Proost et al., 2017); however, these individuals all harbored an additional cardiogenetic variant, including two individuals who each harbored a different pathogenic frameshift variant in the PKP2 gene. This variant has also been reported in one individual diagnosed with DCM, although in this same study, G863R was also found in one control individual (Elliot et al., 2010). Additionally, the G863R variant has been observed in 18/66702 (0.03%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).The G863R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant lacks large segregation studies and functional evidence which would further clarify its role in disease. Furthermore, this variant is also classified as a variant of uncertain significance by multiple other clinical laboratories (ClinVar SCV000063110.4, SCV000290734.2, SCV000320415.1; Landrum et al., 2016).
Integrated Genetics/Laboratory Corporation of America RCV000039426 SCV000919279 uncertain significance not specified 2017-09-05 criteria provided, single submitter clinical testing Variant summary: The DSC2 c.2587G>A (p.Gly863Arg) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have not been confirmed by any in vitro/vivo functional studies. This variant was found in 34/122138 control chromosomes at a frequency of 0.0002784, which is approximately 28 times the estimated maximal expected allele frequency of a pathogenic DSC2 variant (0.00001), suggesting this variant is likely a benign polymorphism. This variant has been reported in affected individuals with DCM or ARVD. One ARVD patient also carried PKP2 variant c.917_918delCC, suggesting variant of interest may not be the primary cause of the phenotype. However, since ARVD is a known clinical entity that sometimes follows a digenic inheritance, we cannot exclude the pathogenicy of variant of interest based on the co-occurrence of PKP2 variant c.917_918delCC. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign unitl more information becomes available.
Invitae RCV000227283 SCV000290734 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 11 2016-12-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 863 of the DSC2 protein (p.Gly863Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs147109895, ExAC 0.04%). This variant has been reported in an individual affected with arrhythmogenic right ventricular dysplasia (PMID: 21606396), however, in that individual a pathogenic allele was also identified in DSC2, which suggests that this c.2587G>A variant was not the primary cause of disease. This variant has also been reported in an individual with dilated cardiomyopathy as well as in an unaffected control (PMID: 20716751). ClinVar contains an entry for this variant (Variation ID: 46183). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, while this variant has been seen in two patients with DSC2-related phenotypes, one of those patients had an alternative explanation for their disease and this variant is report at a higher frequency in controls than expected for DSC2-related diseases. However, the evidence is insufficient at this time to prove conclusively that this variant is not causative. For these reasons, this change has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000039426 SCV000063110 uncertain significance not specified 2016-03-06 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Gly863Arg var iant has been reported in the literature in one individual with DCM and 1 indivi dual with ARVC (Elliott 2010, Cox 2011). This variant has been identified in 0.0 3% (33/121305) of chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs147109895). Computational prediction tools and conservation analysis suggest that the p.Gly863Arg variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain, its f requency suggests that it is more likely to be benign.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000756035 SCV000925065 uncertain significance not provided 2017-03-07 no assertion criteria provided provider interpretation

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