Submissions for variant NM_004415.4(DSP):c.3805C>T (p.Arg1269Ter)

gnomAD frequency: 0.00001  dbSNP: rs767643821

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181316	SCV000233610	pathogenic	not provided	2023-02-02	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26383259, 28436997, 31447099, Glazer2021[preprint], 31402444, 34515413, 23137101)
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709723	SCV000839953	likely pathogenic	Arrhythmogenic right ventricular dysplasia 8	2018-01-09	criteria provided, single submitter	clinical testing	This c.3805C>T variant in the DSP gene is predicted to introduce a premature translation termination codon. It has been reported in three individuals in a family with arrhythmogenic right ventricular cardiomyopathy (ARVC; PMID 23137101). Functional analysis in endomyocardial biopsies of the proband indicates that the mutant transcript is likely to be degraded through nonsense-mediated decay and that DSP protein expression levels are decreased (PMID 23137101). This c.3805C>T, p.Arg1269* variant in the DSP gene is classified as likely pathogenic
Invitae	RCV001388420	SCV001589404	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1269*) in the DSP gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSP are known to be pathogenic (PMID: 20716751, 24503780, 25227139). This variant is present in population databases (rs767643821, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 23137101). ClinVar contains an entry for this variant (Variation ID: 199881). For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000181316	SCV002501378	pathogenic	not provided	2021-08-24	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150054	SCV003837781	pathogenic	Cardiomyopathy	2021-11-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165384	SCV003900135	pathogenic	Cardiovascular phenotype	2023-01-26	criteria provided, single submitter	clinical testing	The p.R1269* pathogenic mutation (also known as c.3805C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 3805. This changes the amino acid from an arginine to a stop codon within coding exon 23. This alteration has been reported in a family with features of arrhythmogenic right ventricular cardiomyopathy (ARVC) (Rasmussen TB et al. Clin Genet, 2013 Jul;84:20-30). This alteration has also been reported in sudden cardiac death and dilated cardiomyopathy (DCM) cohorts (Hertz CL et al. Int J Legal Med, 2016 Jan;130:91-102; Janin A et al. Clin Genet, 2017 Dec;92:616-623). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Alterations in DSP that result in haploinsufficiency or protein truncation have been reported in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM) (Fressart V et al. Europace. 2010;12(6):861-8; Elliott P et al. Circ Cardiovasc Genet. 2010;3(4):314-22; Quarta G et al. Circulation. 2011;123(23):2701-9; Garcia-Pavia P et al. Heart. 2011;97(21):1744-52; Rasmussen TB et al. Clin Genet. 2013;84(1):20-30; Pugh TJ et al. Genet Med. 2014;16(8):601-8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV003150054	SCV004363374	pathogenic	Cardiomyopathy	2023-04-11	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 23 of the DSP gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A study has shown decreased variant transcript and protein expression in keratinocytes and endocardium biopsy samples from carriers, indicating potential haploinsufficiency through nonsense-mediated mRNA decay (PMID: 23137101). This variant has been reported in four individuals from a family affected with arrhythmogenic right ventricular cardiomyopathy, including 1 clinically symptomatic individual, 2 carriers with varying degrees of subclinical phenotype presentations, and 1 asymptomatic carrier (PMID: 23137101). This variant has been identified in 1/250796 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV001028062	SCV001190838	likely pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2020-02-05	no assertion criteria provided	clinical testing