Submissions for variant NM_004415.4(DSP):c.146C>T (p.Thr49Ile)

dbSNP: rs151153655

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001179209	SCV001343820	uncertain significance	Cardiomyopathy	2022-07-12	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 49 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 3/169636 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293560	SCV001482163	uncertain significance	not specified	2021-02-08	criteria provided, single submitter	clinical testing	Variant summary: DSP c.146C>T (p.Thr49Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 169636 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.146C>T in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with a pathogenic variant has been reported (KCNQ1 c.573_577delGCGCT, p.Arg192CysfsX91; Internal testing). A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001751317	SCV001997305	uncertain significance	not provided	2020-01-07	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV003769941	SCV004571636	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-05-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004006543	SCV004822794	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2022-11-28	criteria provided, single submitter	clinical testing