Submissions for variant NM_004415.4(DSP):c.1730T>C (p.Met577Thr)

gnomAD frequency: 0.00001  dbSNP: rs141956992

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000795625	SCV000935093	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2022-02-07	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 577 of the DSP protein (p.Met577Thr). This variant is present in population databases (rs141956992, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with DSP-related conditions. ClinVar contains an entry for this variant (Variation ID: 642208). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002397588	SCV002713753	likely benign	Cardiovascular phenotype	2021-08-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV002469292	SCV002765188	uncertain significance	not provided	2022-12-05	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26582918)
Fulgent Genetics, Fulgent Genetics	RCV002501048	SCV002812794	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	2021-08-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003532263	SCV004363307	uncertain significance	Cardiomyopathy	2021-08-30	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 577 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 1/251340 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.