Submissions for variant NM_004415.4(DSP):c.8500C>T (p.Arg2834Cys)

gnomAD frequency: 0.00004  dbSNP: rs753033333

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202757	SCV000257972	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2015-07-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000480458	SCV000565934	uncertain significance	not provided	2022-04-15	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; This variant is associated with the following publications: (PMID: 26582918)
Invitae	RCV000821527	SCV000962286	likely benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444822	SCV002679009	uncertain significance	Cardiovascular phenotype	2022-12-27	criteria provided, single submitter	clinical testing	The p.R2834C variant (also known as c.8500C>T), located in coding exon 24 of the DSP gene, results from a C to T substitution at nucleotide position 8500. The arginine at codon 2834 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a family with dilated cardiomyopathy (DCM) that also had alterations in other cardiac-related genes (Hoorntje ET et al. Circ Cardiovasc Genet, 2017 Aug;10:). Another alteration affecting the same amino acid, p.R2834H (c.8501G>A), has been reported in association with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Yang Z et al. Circ. Res., 2006 Sep;99:646-55). 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	RCV002500638	SCV002800954	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	2021-11-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003532050	SCV004363544	uncertain significance	Cardiomyopathy	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2834 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 an individual affected with dilated cardiomyopathy (Posafalvi 2015, dissertation, University of Groningen). This variant has also been reported in two individuals from a family affected with mild dilated cardiomyopathy, conduction disease and atrial fibrillation, who also carried a pathogenic variant in the LMNA gene that could explain the observed phenotypes (PMID: 28790152). This variant has been identified in 9/277786 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000480458	SCV001740931	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000480458	SCV001967940	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000480458	SCV002034177	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000480458	SCV002034491	uncertain significance	not provided		no assertion criteria provided	clinical testing