ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.4531C>T (p.Gln1511Ter)

gnomAD frequency: 0.00001  dbSNP: rs397516940
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256151 SCV000322042 pathogenic not provided 2022-12-28 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: 31317183, 31402444, 32372669, 31386562, 26569459, 33460606, 34352074)
Invitae RCV000528916 SCV000639740 pathogenic Arrhythmogenic cardiomyopathy with wooly hair and keratoderma; Arrhythmogenic right ventricular dysplasia 8 2023-08-22 criteria provided, single submitter clinical testing This variant is present in population databases (rs397516940, gnomAD 0.05%). This sequence change creates a premature translational stop signal (p.Gln1511*) 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 premature translational stop signal has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (PMID: 31386562). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 44914).
Color Diagnostics, LLC DBA Color Health RCV001184211 SCV001350151 pathogenic Cardiomyopathy 2023-02-23 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. This variant has been reported in two unrelated individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 26569459, 31386562), in one individual affected with dilated cardiomyopathy (PMID: 31317183), and in one individual suspected of having hereditary cardiomyopathies (PMID: 35083019). This variant has been identified in 5/249842 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.
Ambry Genetics RCV002336137 SCV002637174 pathogenic Cardiovascular phenotype 2022-08-30 criteria provided, single submitter clinical testing The p.Q1511* pathogenic mutation (also known as c.4531C>T), located in coding exon 23 of the DSP gene, results from a C to T substitution at nucleotide position 4531. This changes the amino acid from a glutamine to a stop codon within coding exon 23. This alteration has been associated in the literature with cardiovascular disease (Akdis D et al. Heart Rhythm, 2016 Mar;13:731-41; van Lint FHM et al. Circ Genom Precis Med, 2019 08;12:e002467; Augusto JB et al. Eur Heart J Cardiovasc Imaging, 2020 03;21:326-336; Reza N et al. Cardiogenetics, 2022 Mar;12:24-36). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000038049 SCV000061715 likely pathogenic Arrhythmogenic right ventricular cardiomyopathy 2015-04-23 no assertion criteria provided clinical testing The p.Gln1511X variant in DSP has been previously identified by our laboratory i n 1 adult with features of HCM and ARVC as well as right bundle branch block (RB BB). It has also been identified in 4/65986 European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516940). This nonsense variant leads to a premature termination codon at position 1511, w hich is predicted to lead to a truncated or absent protein. Frameshift and nonse nse variants in DSP have been well reported in patients with ARVC (http://arvcda tabase.info/), but recent evidence supports that they can also cause DCM (Pugh 2 014). In summary, although additional studies are required to fully establish it s clinical significance, the p.Gln1511X variant is likely pathogenic.

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