ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.4514C>T (p.Ala1505Val) (rs375919492)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000218906 SCV000271728 uncertain significance not specified 2015-08-12 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ala1505Val va riant in DSP has not been previously reported in individuals with cardiomyopathy , but has been identified in 6/65984 European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs375919492). Alanine (Ala) at position 1505 is not conserved in evolution and 2 mammals and 1 amphib ian (squirrel, Wedell seal, and X. tropicalis) carry a valine (Val), raising the possibility that this change may be tolerated. Although this suggests that the variant may not impact the protein, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Al a1505Val variant is uncertain, these data suggest that it is more likely to be b enign.
Invitae RCV000641799 SCV000763449 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-08-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1505 of the DSP protein (p.Ala1505Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs375919492, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 20031617). ClinVar contains an entry for this variant (Variation ID: 228642). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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