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

gnomAD frequency: 0.00021  dbSNP: rs762561997

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766882	SCV000233621	uncertain significance	not provided	2019-12-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance by another clinical laboratory (ClinVar Variant ID#199888; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32880476)
Invitae	RCV000686543	SCV000814065	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-11-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001179619	SCV001344327	uncertain significance	Cardiomyopathy	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1679 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/250894 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002336447	SCV002644369	uncertain significance	Cardiovascular phenotype	2020-09-02	criteria provided, single submitter	clinical testing	The p.H1679Y variant (also known as c.5035C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 5035. The histidine at codon 1679 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766882	SCV001739973	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766882	SCV001953398	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766882	SCV001967596	uncertain significance	not provided		no assertion criteria provided	clinical testing