Submissions for variant NM_004415.4(DSP):c.3465G>C (p.Trp1155Cys)

dbSNP: rs1759354150

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001297009	SCV001485990	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2022-07-11	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1155 of the DSP protein (p.Trp1155Cys). This variant is not present in population databases (gnomAD no frequency). 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: 1000822). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
Color Diagnostics, LLC DBA Color Health	RCV003532929	SCV004363362	uncertain significance	Cardiomyopathy	2023-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with cysteine at codon 1155 of the DSP protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 not been identified 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.
All of Us Research Program, National Institutes of Health	RCV004004969	SCV004830211	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with cysteine at codon 1155 of the DSP protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 not been identified 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	RCV004731121	SCV005340490	uncertain significance	DSP-related disorder	2024-09-21	no assertion criteria provided	clinical testing	The DSP c.3465G>C variant is predicted to result in the amino acid substitution p.Trp1155Cys. This variant has been reported as a variant of uncertain significance in a cohort of individuals with syncope and/or sudden cardiac arrest; however, detailed clinical information was not available (Vokač et al. 2024. PubMed ID: 38254962). This variant has not been reported in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.