Submissions for variant NM_004415.4(DSP):c.7552G>A (p.Val2518Ile)

gnomAD frequency: 0.00008  dbSNP: rs757394666

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000236392	SCV000294315	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-11-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001181789	SCV001347015	uncertain significance	Cardiomyopathy	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 2518 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 been reported in an individual with ventricular fibrillation and an individual with arrhythmia (PMID: 29032884, Color internal data). This variant has been identified in 9/282880 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	RCV002392736	SCV002675193	uncertain significance	Cardiovascular phenotype	2024-08-30	criteria provided, single submitter	clinical testing	The p.V2518I variant (also known as c.7552G>A), located in coding exon 24 of the DSP gene, results from a G to A substitution at nucleotide position 7552. The valine at codon 2518 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in an idiopathic ventricular fibrillation cohort (Leinonen JT et al. Int J Cardiol, 2018 Jan;250:139-145). This variant has also been reported in a hypertrophic cardiomyopathy (HCM) and a cardiac conditions cohort (Carlo S et al. Cureus, 2022 Mar;14:e23349; Fernandez-Falgueras A et al. PLoS One, 2024 May;19:e0297914). This amino acid position is 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.
Revvity Omics, Revvity	RCV003144172	SCV003829137	uncertain significance	not provided	2022-06-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998938	SCV004816609	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 2518 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 been reported in an individual with ventricular fibrillation and an individual with arrhythmia (PMID: 29032884, Color internal data). This variant has been identified in 9/282880 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.
PreventionGenetics, part of Exact Sciences	RCV003977702	SCV004790103	uncertain significance	DSP-related disorder	2023-12-13	no assertion criteria provided	clinical testing	The DSP c.7552G>A variant is predicted to result in the amino acid substitution p.Val2518Ile. This variant has been reported in an individual with idiopathic ventricular fibrillation and in another individual with hypertrophic cardiomyopathy, although additional variants were identified in cardiac-related genes in these individuals (Patient I34, Leinonen et al. 2018. PubMed ID: 29032884; Carlo et al. 2022. PubMed ID: 35475074). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.