Submissions for variant NM_004415.4(DSP):c.6247C>T (p.Arg2083Cys)

gnomAD frequency: 0.00019  dbSNP: rs370093129

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769236	SCV000900612	uncertain significance	Cardiomyopathy	2017-06-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781334	SCV000919293	uncertain significance	not specified	2017-09-07	criteria provided, single submitter	clinical testing	Variant summary: The DSP c.6247C>T (p.Arg2083Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 13/276998 control chromosomes at a frequency of 0.0000469, which does not exceed the estimated maximal expected allele frequency of a pathogenic DSP variant (0.0002). This variant has been reported in one LQTS patient who carries a KCNH2 variant (c.2863C>G/p.L955V, classified likely pathogenic in ClinVar). Taken together, this variant is classified as VUS.
Color Diagnostics, LLC DBA Color Health	RCV000769236	SCV001339624	uncertain significance	Cardiomyopathy	2023-03-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2083 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 been reported in an individual affected with long QT syndrome (PMID: 24981977); this individual also carried a variant in the KCNH2 gene with conflicting interpretations in ClinVar (variation ID67445) and thus uncertain impact on the observed phenotype. The DSP p.Arg2083Cys variant has been identified in 12/282646 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	RCV001240930	SCV001413913	benign	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002360875	SCV002658672	uncertain significance	Cardiovascular phenotype	2022-09-23	criteria provided, single submitter	clinical testing	The p.R2083C variant (also known as c.6247C>T), located in coding exon 24 of the DSP gene, results from a C to T substitution at nucleotide position 6247. The arginine at codon 2083 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant co-occurred with a variant in the KCNH2 gene in an individual reported to have long QT syndrome; however, details were limited (Brion M et al. Electrophoresis, 2014 Nov;35:3111-6). This amino acid position is well 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	RCV002485983	SCV002791670	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	2022-04-05	criteria provided, single submitter	clinical testing