Submissions for variant NM_004415.4(DSP):c.4198C>T (p.Arg1400Ter)

dbSNP: rs770873593

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181321	SCV000233616	pathogenic	not provided	2023-06-02	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in patients with ARVC in the published literature (Bao et al., 2013; Imamura et al., 2021), and in compound heterozygous state in a patient with severe left sided heart failure and cutaneous abnormalities that also harbored a second pathogenic variant in the DSP gene (Antonov et al., 2015); 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: 31402444, 34135346, 24125834, 25516398, 32877757, 29178656, 33996946)
Invitae	RCV000697999	SCV000826637	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1400*) 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 (rs770873593, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy and/or desmosomal cardiocutaneous syndromes (PMID: 24125834, 25516398). ClinVar contains an entry for this variant (Variation ID: 199884). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001176347	SCV001340311	pathogenic	Cardiomyopathy	2018-11-09	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. To our knowledge, functional assays have not been performed for this variant. This variant was reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 29178656), and in a 3-year-old boy affected with severe heart failure and cutaneous abnormalities in compound heterozygosity with p.Arg2284* (PMID: 25516398). This variant has been identified in 1/246122 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of DSP function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256837	SCV001433322	pathogenic	Dilated cardiomyopathy 1A	2020-02-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001336684	SCV001530135	likely pathogenic	Arrhythmogenic right ventricular dysplasia 8	2018-02-26	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002326982	SCV002626653	pathogenic	Cardiovascular phenotype	2023-05-26	criteria provided, single submitter	clinical testing	The p.R1400* pathogenic mutation (also known as c.4198C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 4198. This changes the amino acid from an arginine to a stop codon within coding exon 23. This mutation has been detected once in an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort as well as in a three year old male with left-sided heart failure, cutaneous abnormalities, and palmoplantar keratoderma (PPK) who also carried DSP R2284* (Bao J et al. Circ Cardiovasc Genet, 2013 Dec;6:552-6; Antonov NK et al. Pediatr Dermatol Dec;32:102-8). In addition to the clinical data presented in the literature, 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.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV001256837	SCV002769818	pathogenic	Dilated cardiomyopathy 1A	2022-12-26	criteria provided, single submitter	clinical testing	We observed a homozygous c.4198C>T (p.R1400*) genetic variant in the DSP gene in a 4-y.o. female proband (of consanguineous marriage) diagnosed with dilated cardiomyopathy and thrombosis. According to NMD Esc Predictor, mRNA carrying this variant will be processed through nonsense-mediated decay mechanism, leading to haploinsufficiency. This variant is not observed at significant frequency in large population cohorts (gnomAD). ClinVar contains an entry for this variant (Variation ID: 199884). This genetic variant in heterozygous state was reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 24125834, 29178656), and in a 3-y.o. male proband affected with severe heart failure and cutaneous abnormalities in compound heterozygosity with p.Arg2284* (PMID: 25516398). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002500527	SCV002811120	pathogenic	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	2021-08-03	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001336684	SCV004046448	pathogenic	Arrhythmogenic right ventricular dysplasia 8	2023-01-17	criteria provided, single submitter	clinical testing	The c.4198C>T variant identified in this individual has previously been reported in at least two individuals with arrhythmogenic right ventricular cardiomyopathy [PMID: 24125834, 29178656], in an individual with dilated cardiomyopathy [PMID: 33996946], and in a 3-year-old boy affected with severe heart failure and cutaneous abnormalities in compound heterozygosity with p.(Arg2284Ter) [PMID: 25516398]. The c.4198C>T variant has been deposited in ClinVar [ClinVar ID: 199884] as Pathogenic (8 entries) and Likely Pathogenic (1 entry). The c.4198C>T variant is observed in 4 alleles (0.0006% minor allele frequency with 0homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.4198C>T variant is located in exon 23 of this 24-exon gene, predicted to incorporate a premature termination codon (p.(Arg1400Ter)), and is expected to result in loss-of-function via nonsense-mediated decay. Based on available evidence this c.4198C>T p.(Arg1400Ter) variant identified in DSP is classified as Pathogenic.
Gharavi Laboratory, Columbia University	RCV000181321	SCV000809456	pathogenic	not provided	2018-09-16	no assertion criteria provided	research