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

gnomAD frequency: 0.00001  dbSNP: rs748790273

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000457295	SCV000543221	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-12-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001159661	SCV001321387	uncertain significance	Lethal acantholytic epidermolysis bullosa	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001159662	SCV001321388	uncertain significance	Woolly hair-skin fragility syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001161048	SCV001322891	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001184030	SCV001349902	likely benign	Cardiomyopathy	2020-07-15	criteria provided, single submitter	clinical testing
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 (http://exac.broadinstitute.org/), 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.