Submissions for variant NM_004415.4(DSP):c.8495G>T (p.Gly2832Val)

gnomAD frequency: 0.00001  dbSNP: rs397516970

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171925	SCV000055174	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038111	SCV000061777	uncertain significance	not specified	2012-05-02	criteria provided, single submitter	clinical testing	The Gly2832Val variant (DSP) has not been reported in the literature. It has bee n identified by our laboratory in one individual with DCM, but did not segregate with disease in one affected relative, arguing against a pathogenic role. Compu tational analyses (biochemical amino acid properties, conservation, AlignGVGD, P olyPhen2, and SIFT) do not provide strong support for or against an impact to th e protein. this variant has not been identified in a very large and broad popula tion by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). T his low frequency is consistent with a disease causing role, but is insufficient to establish this with certainty. Additional information is needed to fully ass ess the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV001177324	SCV001341518	uncertain significance	Cardiomyopathy	2023-06-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 2832 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 one individual affected with dilated cardiomyopathy, who also carried a pathogenic splicing variant in the same gene that could explain the observed phenotype (PMID: 24503780, 27532257). This variant has been identified in 1/247058 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003764680	SCV004604886	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-08-30	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 44974). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). This variant is present in population databases (rs397516970, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2832 of the DSP protein (p.Gly2832Val). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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.
All of Us Research Program, National Institutes of Health	RCV003996359	SCV004814292	uncertain significance	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 2832 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 one individual affected with dilated cardiomyopathy, who also carried a pathogenic splicing variant in the same gene that could explain the observed phenotype (PMID: 24503780, 27532257). This variant has been identified in 1/247058 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.