ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.1483G>A (p.Val495Met) (rs372014020)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619701 SCV000739867 uncertain significance Cardiovascular phenotype 2013-05-30 criteria provided, single submitter clinical testing
Color RCV000776308 SCV000911629 likely benign Cardiomyopathy 2018-04-07 criteria provided, single submitter clinical testing
GeneDx RCV000766808 SCV000571232 uncertain significance not provided 2019-01-18 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DSP gene. The V495M variant has been previously reported in one individual with HCM (Lopes et al., 2015), and is classified as a variant of uncertain significance in ClinVar by a different clinical laboratory in association with cardiomyopathy in one other individual (ClinVar SCV000271720.1; Landrum et al., 2016). However, further clinical, family history or segregation data was not available for either of these reported individuals. The V495M variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the V495M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Integrated Genetics/Laboratory Corporation of America RCV000220212 SCV000919286 likely benign not specified 2018-06-04 criteria provided, single submitter clinical testing Variant summary: DSP c.1483G>A (p.Val495Met) results in a conservative amino acid change in the SH3 domain (IPR001452) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 277194 control chromosomes, in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals (0.0033) in the gnomAD database is approximately 330 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1483G>A has been reported in the literature in an individual affected with hypertrophic cardiomyopathy (Lopes 2013). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000692937 SCV000820788 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-03-10 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 495 of the DSP protein (p.Val495Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs372014020, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 228635). 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 C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000220212 SCV000271720 likely benign not specified 2018-04-10 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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