ClinVar Miner

Submissions for variant NM_004415.4(DSP):c.4531C>T (p.Gln1511Ter) (rs397516940)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000256151 SCV000322042 pathogenic not provided 2018-08-30 criteria provided, single submitter clinical testing The Q1511X pathogenic variant in the DSP gene has been reported as disease-causing in one individual with definitive ARVC, whose clinical presentation included ventricular fibrillation, sudden cardiac arrest and a left ventricular ejection fraction of 30% (Akdis et al., 2016). Additionally, the Q1511X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Q1511X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Furthermore, other downstream nonsense variants in the DSP gene have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014). In summary, Q1511X in the DSP gene is interpreted as a pathogenic variant.
Invitae RCV000528916 SCV000639740 pathogenic Dilated cardiomyopathy with woolly hair and keratoderma; Arrhythmogenic right ventricular cardiomyopathy, type 8 2018-07-16 criteria provided, single submitter clinical testing 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. This variant is present in population databases (rs397516940, ExAC 0.006%). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 44914). Loss-of-function variants in DSP are known to be pathogenic (PMID: 16061754, 20716751, 24503780). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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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