Submissions for variant NM_004415.4(DSP):c.4696C>G (p.Leu1566Val)

gnomAD frequency: 0.00004  dbSNP: rs201785897

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498070	SCV000590371	uncertain significance	not provided	2017-06-12	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DSP gene. The L1566V variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. However, the L1566V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792630	SCV000931936	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2025-01-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001185498	SCV001351723	uncertain significance	Cardiomyopathy	2024-03-25	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1566 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function. 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 7/250376 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262576	SCV001440498	uncertain significance	Arrhythmogenic right ventricular dysplasia 8	2019-01-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001185498	SCV002043295	uncertain significance	Cardiomyopathy	2021-04-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002341176	SCV002639993	uncertain significance	Cardiovascular phenotype	2025-02-05	criteria provided, single submitter	clinical testing	The p.L1566V variant (also known as c.4696C>G), located in coding exon 23 of the DSP gene, results from a C to G substitution at nucleotide position 4696. The leucine at codon 1566 is replaced by valine, an amino acid with highly similar properties. This variant was has been detected in a peripartum cardiomyopathy cohort (Goli R et al. Circulation, 2021 May;143:1852-1862). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV004003506	SCV004818597	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1566 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 7/250376 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000498070	SCV005197783	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing