Submissions for variant NM_004415.4(DSP):c.7924G>A (p.Val2642Ile)

gnomAD frequency: 0.00002  dbSNP: rs869025397

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208142	SCV000263883	uncertain significance	Primary familial hypertrophic cardiomyopathy	2015-12-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220371	SCV000271743	uncertain significance	not specified	2015-03-04	criteria provided, single submitter	clinical testing	The p.Val2642Ile variant in DSP has not been previously identified in individual s with cardiomyopathy or in large population studies. Computational prediction t ools and conservation analysis does not provide strong evidence for or against a n impact the protein. In summary, the clinical significance of the p.Val2642Ile variant is uncertain.
Invitae	RCV000469566	SCV000543234	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-05-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001185751	SCV001352026	uncertain significance	Cardiomyopathy	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 2642 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 4/250910 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.
GeneDx	RCV001762452	SCV001990835	uncertain significance	not provided	2019-04-02	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 222587; Landrum et al., 2016)
Fulgent Genetics, Fulgent Genetics	RCV002485359	SCV002786190	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8; Lethal acantholytic epidermolysis bullosa; Woolly hair-skin fragility syndrome; Keratosis palmoplantaris striata 2; Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis	2021-10-11	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001185751	SCV003837793	uncertain significance	Cardiomyopathy	2021-11-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000220371	SCV003844632	uncertain significance	not specified	2023-02-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298272	SCV003996575	uncertain significance	Cardiovascular phenotype	2023-04-06	criteria provided, single submitter	clinical testing	The p.V2642I variant (also known as c.7924G>A), located in coding exon 24 of the DSP gene, results from a G to A substitution at nucleotide position 7924. The valine at codon 2642 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). This amino acid position is highly 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.