ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.1562A>C (p.Asp521Ala) (rs748790273)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457295 SCV000543221 uncertain significance Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2016-06-11 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 521 of the DSP protein (p.Asp521Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is present in population databases (rs748790273, ExAC 0.03%). This variant has been reported in an individual with sudden unexplained nocturnal death (PMID: 26585738). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786125 SCV000924787 uncertain significance not provided 2016-08-02 no assertion criteria provided provider interpretation p.Asp521Ala (c.1562A>C) in exon 12 of DSP (NM_004415.2) We have seen this variant in an Asian adult with unexplained cardiac arrest. Given the poor gene-phenotype match, the weak case data, the in silico predictions as tolerated, and the presence in ExAC samples of the same ancestral origin as the patient and reported case, we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Zhao et al reported the variant in a case of sudden unexplained nocturnal death in their Chinese cohort. This was the only case I could find. There are no ClinVar entries. Per the lab report, "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT,, Align-GVGD) all suggest that this variant is likely to be tolerated." The variant was reported online in 3 of 60704 individuals in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of August 2nd, 2016). Specifically, the variant was observed in 3 of 4327 (AF 0.0003467) East Asian. The phenotype of those individuals 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.

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