ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.1273C>T (p.Arg425Ter)

dbSNP: rs397516915
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000208168 SCV000061655 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2019-04-29 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Blueprint Genetics RCV000208168 SCV000263866 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-04-23 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000770234 SCV000901665 likely pathogenic Cardiomyopathy 2015-09-28 criteria provided, single submitter clinical testing
Undiagnosed Diseases Network, NIH RCV000991215 SCV001142595 pathogenic DSP-related arrhythmogenic cardiomyopathy 2019-08-14 criteria provided, single submitter clinical testing
Invitae RCV001056868 SCV001221333 pathogenic Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2023-08-01 criteria provided, single submitter clinical testing This premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 22555271). This variant is present in population databases (rs397516915, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg425*) 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). ClinVar contains an entry for this variant (Variation ID: 44856). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001813751 SCV002061004 likely pathogenic not provided 2021-12-22 criteria provided, single submitter clinical testing Identified in a family with ARVC in the published literature (Kindel et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); 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; Reported in ClinVar (ClinVar Variant ID# 44856; ClinVar); This variant is associated with the following publications: (PMID: 31402444, 22555271, 26582918, 27535533)
Ambry Genetics RCV002371832 SCV002686138 pathogenic Cardiovascular phenotype 2021-07-08 criteria provided, single submitter clinical testing The p.R425* pathogenic mutation (also known as c.1273C>T), located in coding exon 11 of the DSP gene, results from a C to T substitution at nucleotide position 1273. This changes the amino acid from an arginine to a stop codon within coding exon 11. This variant was reported in an individual with familial arrhythmogenic right ventricular cardiomyopathy (ARVC) (Kindel SJ et al. J Card Fail, 2012 May;18:396-403). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003330410 SCV004037639 pathogenic Familial isolated arrhythmogenic right ventricular dysplasia 2023-08-28 criteria provided, single submitter clinical testing Variant summary: DSP c.1273C>T (p.Arg425X) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251268 control chromosomes (gnomAD). c.1273C>T has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (Kindel_2012, Protonotarios_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22555271, 35766183, 35653365). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=3) and likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic.

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