Submissions for variant NM_004415.4(DSP):c.249G>A (p.Met83Ile)

gnomAD frequency: 0.00001  dbSNP: rs1426930663

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623911	SCV000740333	uncertain significance	Primary familial dilated cardiomyopathy	2017-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001181568	SCV001346745	uncertain significance	Cardiomyopathy	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 83 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 DSP-related disorders in the literature. This variant has been identified in 1/31408 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	RCV001584447	SCV001813816	uncertain significance	not provided	2020-03-30	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 (ClinVar Variant ID# 520443; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531870	SCV003457694	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2025-01-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162761	SCV003867546	uncertain significance	Cardiovascular phenotype	2022-11-04	criteria provided, single submitter	clinical testing	The p.M83I variant (also known as c.249G>A), located in coding exon 2 of the DSP gene, results from a G to A substitution at nucleotide position 249. The methionine at codon 83 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is conserved. 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.
CeGaT Center for Human Genetics Tuebingen	RCV001584447	SCV004163038	uncertain significance	not provided	2022-05-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004002744	SCV004826651	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 83 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 DSP-related disorders in the literature. This variant has been identified in 1/31408 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.