Submissions for variant NM_004415.4(DSP):c.3799C>T (p.Arg1267Ter)

dbSNP: rs121912997

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000598733	SCV000709901	pathogenic	not provided	2022-10-10	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in association with DCM and arrhythmogenic cardiomyopathy; however, patient-specific details were not provided (Marschall et al., 2019; Reza et al., 2022); 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: 25525159, 16467215, 34426522, 30398466, 31737537, 30993396, 31073624, 34691145, 35083019)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851909	SCV002235985	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1267*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with clinical features of Carvajal syndrome (PMID: 16467215, 30993396). ClinVar contains an entry for this variant (Variation ID: 16845). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002354165	SCV002620131	pathogenic	Cardiovascular phenotype	2023-10-23	criteria provided, single submitter	clinical testing	The p.R1267* pathogenic mutation (also known as c.3799C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 3799. This changes the amino acid from an arginine to a stop codon within coding exon 23. 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 particular variant has been reported in the homozygous state in a subject with left and right ventricular involvement, wooly hair and palmar keratoderma (Uzumcu A et al. J. Med. Genet., 2006 Feb;43:e5). This variant has also been reported in the compound heterozygous state in two siblings with dilated cardiomyopathy (DCM) (Surmacz R et al. Pol. Arch. Intern. Med., 2018 12;128:785-787). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV003531904	SCV004363372	pathogenic	Cardiomyopathy	2023-08-21	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 with skin biopsies from carrier individuals has shown that this variant causes an absent expression of the major DSP transcript (NM_004415) in the heart (PMID: 16467215). This variant has been reported in homozygous state in an individual affected with arrhythmogenic cardiomyopathy with epidermolytic palmoplantar keratoderma and wooly hair (PMID: 16467215), and in compound heterozygous state with another DSP pathogenic variant in an individual affected with arrhythmogenic-dilated cardiomyopathy with epidermolytic palmoplantar keratoderma and wooly hair (PMID: 30993396). This variant has also been reported in compound heterozygous state with a DSP variant of uncertain significance in two twin brothers affected with early-onset dilated cardiomyopathy (PMID: 30398466), and in heterozygous state in an individual suspected of having hereditary cardiomyopathy (PMID: 35083019) as well as in five asymptomatic individuals (PMID: 16467215, 30398466, 30993396). This variant has not been identified 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.
All of Us Research Program, National Institutes of Health	RCV000018339	SCV004836942	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2023-10-02	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 with skin biopsies from carrier individuals has shown that this variant causes an absent expression of the major DSP transcript (NM_004415) in the heart (PMID: 16467215). This variant has been reported in homozygous state in an individual affected with arrhythmogenic cardiomyopathy with epidermolytic palmoplantar keratoderma and wooly hair (PMID: 16467215), and in compound heterozygous state with another DSP pathogenic variant in an individual affected with arrhythmogenic-dilated cardiomyopathy with epidermolytic palmoplantar keratoderma and wooly hair (PMID: 30993396). This variant has also been reported in compound heterozygous state with a DSP variant of uncertain significance in two twin brothers affected with early-onset dilated cardiomyopathy (PMID: 30398466), and in heterozygous state in an individual suspected of having hereditary cardiomyopathy (PMID: 35083019) as well as in five asymptomatic individuals (PMID: 16467215, 30398466, 30993396). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000018339	SCV005184929	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2024-05-10	criteria provided, single submitter	clinical testing	Variant summary: DSP c.3799C>T (p.Arg1267X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250804 control chromosomes. c.3799C>T has been reported in the literature in individuals affected with Carvajal Syndrome and dilated Cardiomyopathy (Uzumcu_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 16467215). ClinVar contains an entry for this variant (Variation ID: 16845). Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000598733	SCV005197781	likely pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786273	SCV005400111	pathogenic	Primary dilated cardiomyopathy	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with DSP-related cardiac disorders including arrhythmogenic right ventricular dysplasia 8 (MIM#607450) and dilated cardiomyopathy (MONDO#0005021), DSP-related. (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene are usually inherited in a dominant manner, however rare reports of recessive inheritance have resulted in a more severe cardiac phenotype (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. In families with cardiomyopathies, reduced penetrance has been reported among family members aged 60-86 years (preprint by Hoorntje, E.T. et al. (2021)). (I) 0115 - Variants in this gene are known to have variable expressivity. Age-dependent penetrance and variable expressivity are well-described aspects of arrhythmogenic cardiomyopathy (PMID: 29062697). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0702 - Other premature termination variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). At least nine comparable NMD-predicted variants have been reported in individuals with sudden death or DSP-related cardiac conditions (VCGS, ClinVar, PMIDs: 26383259, 27532257, 29915097). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic/pathogenic by multiple clinical testing laboratories (ClinVar). It has also been reported in individuals with DSP-related cardiac conditions (PMIDs: 35083019, 30398466, 30993396). In addition, it has been reported in asymptomatic family members (PMIDs: 30398466, 30993396). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000018339	SCV000038618	pathogenic	Arrhythmogenic cardiomyopathy with wooly hair and keratoderma	2006-02-01	no assertion criteria provided	literature only
Blueprint Genetics	RCV000157195	SCV000206919	likely pathogenic	Primary dilated cardiomyopathy; Long QT syndrome	2014-07-10	no assertion criteria provided	clinical testing