ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.1399C>T (p.Arg467Ter) (rs794728537)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182227 SCV000234530 pathogenic not provided 2016-01-11 criteria provided, single submitter clinical testing The Arg594Stop mutation in the KCNQ1 gene has been reported in association with LQTS (Stattin et al., 2012). Also, Arg594Stop has been observed in other unrelated individuals tested for LQTS at GeneDx. Arg594Stop 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. This mutation is predicted to cause loss of normal protein function either through abnormal, prematurely truncated protein, or by absence of protein product due to nonsense-mediated mRNA decay. Other nonsense mutations in KCNQ1 (Gln530Stop, Gln531Stop, Tyr536Stop, Gln601Stop, Tyr662Stop) have been reported in association with LQTS
Invitae RCV000815960 SCV000956441 pathogenic Long QT syndrome 2018-09-11 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the KCNQ1 gene (p.Arg594*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 83 amino acids of the KCNQ1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual referred for long QT syndrome testing (PMID: 23098067). ClinVar contains an entry for this variant (Variation ID: 200858). This variant disrupts the C-terminus of the KCNQ1 protein. Other variant(s) that disrupt this region (p.Arg632Glnfs*20) have been determined to be pathogenic (PMID: 10024302, 23098067, 23631430, 25187895, 19825999, 16981927). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001449795 SCV001653077 likely pathogenic Congenital long QT syndrome 2020-02-07 criteria provided, single submitter clinical testing The p.Arg594X variant in KCNQ1 has been reported in 2 individuals with long QT syndrome (LQTS; Stattin 2012, Itoh 2015). It was also reported in a neonate with bradycardia and prolonged QT interval and her asymptomatic mother who was 29 years old at the time of testing (Qureshi 2015). Additionally, this variant has been reported by other clinical laboratories in ClinVar (Variation ID 200858). It is absent from large population studies. This nonsense variant leads to a premature termination codon at position 594. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing 12% of the coding region, with 84 amino acids removed. Loss-of-function variants in KCNQ1 downstream of the p.Arg594X variant have been reported in individuals with LQTS. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant LQTS. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PS4_Supporting.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000770826 SCV000902325 likely pathogenic Long QT syndrome 1 2019-02-26 no assertion criteria provided case-control

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