ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.5035C>T (p.His1679Tyr) (rs762561997)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766882 SCV000233621 uncertain significance not provided 2018-10-16 criteria provided, single submitter clinical testing p.His1679Tyr (CAC>TAC): c.5035 C>T in exon 23 of the DSP gene (NM_004415.2). The H1679Y variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H1679Y variant was not observed 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. The H1679Y variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Only one missense mutation in a nearby residue (S1658F) has been reported in association with ARVC. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Invitae RCV000686543 SCV000814065 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-03-16 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 1679 of the DSP protein (p.His1679Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs762561997, ExAC 0.01%). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199888). 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: "Benign"; Align-GVGD: "Class C15"). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000181325 SCV000280091 uncertain significance not specified 2014-07-30 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. Given the lack of known gene-phenotype association and the lack of case data (reviewed below) we consider this variant a variant of uncertain significance. The variant is novel. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The histidine at codon 1679 is mostly conserved across species, with a serine in one lower species. There is other variant reported in association with disease at a nearby codons (p.Ser1658Phe, from HGMD). The variant was reported online in 1 of 60,886 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of December 1, 2014). The phenotype of that individual is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012).

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