Submissions for variant NM_004415.4(DSP):c.6397G>A (p.Gly2133Ser)

gnomAD frequency: 0.00002  dbSNP: rs372393122

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766888	SCV000233637	uncertain significance	not provided	2023-05-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000181340	SCV000271739	uncertain significance	not specified	2015-12-10	criteria provided, single submitter	clinical testing	The p.Gly2133Ser variant in DSP has not been previously reported in individuals with cardiomyopathy, but has been identified in 4/8620 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s372393122). Computational prediction tools and conservation analysis suggest th at the p.Gly2133Ser variant may impact the protein, though this information is n ot predictive enough to determine pathogenicity. In summary, the clinical signif icance of the p.Gly2133Ser variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000181340	SCV000919289	uncertain significance	not specified	2018-01-25	criteria provided, single submitter	clinical testing	Variant summary: The DSP c.6397G>A (p.Gly2133Ser) variant involves the alteration of a conserved nucleotide located at the Plectin repeat domain of the protein (InterPro). 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index, Polyphen not accessible at the time of evaluation). This variant was found in 9/276996 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.000424 (8/18860). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.0002), suggesting this is possibly a benign polymorphism found primarily in the populations of East Asian origin. Although the gnomAD dataset possibly includes cardio patients, thus this frequency needs to be taken with caution. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. One internal sample also carried a likely pathogenic variant in DSP, c.1825C>T/p.Gln609X, suggesting non-pathgoenic role of this variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a VUS-possibly benign until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV001179588	SCV001344287	uncertain significance	Cardiomyopathy	2023-11-09	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 2133 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 9/282650 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.
Invitae	RCV001227095	SCV001399434	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354472	SCV002655308	uncertain significance	Cardiovascular phenotype	2023-08-29	criteria provided, single submitter	clinical testing	The p.G2133S variant (also known as c.6397G>A), located in coding exon 24 of the DSP gene, results from a G to A substitution at nucleotide position 6397. The glycine at codon 2133 is replaced by serine, an amino acid with similar properties. This variant has been detected in a dilated cardiomyopathy genetic testing cohort (Mazzarotto F et al. Circulation. 2020 Feb;141(5):387-398). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002485191	SCV002785950	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	2021-08-24	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002485191	SCV003919902	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	2021-03-30	criteria provided, single submitter	clinical testing	DSP NM_004415.3 exon 24 p.Gly2133Ser (c.6397G>A): This variant has not been reported in the literature but is present in 8/18860 East Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs372393122). This variant is present in ClinVar (Variation ID:199901). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678705	SCV000804869	uncertain significance	Left ventricular noncompaction cardiomyopathy	2016-03-22	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000766888	SCV001921075	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766888	SCV001962899	uncertain significance	not provided		no assertion criteria provided	clinical testing