ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.232G>A (p.Val78Met) (rs151344631)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000057723 SCV000234397 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing The V205M variant in the KCNQ1 gene has been reported previously in two unrelated individuals with LQTS and in 22 family members from a First Nations community of northern British Columbia (Arbour et al., 2008). V205M was reported in individuals with prolonged QTc intervals, but with incomplete penetrance within their families (Arbour et al., 2008; Jackson et al., 2014). This variant has also been reported in one patient in the Jackson Heart Study cohort who had a prolonged QTc interval (Natarajan et al., 2016). Although the V205M variant results in a conservative amino acid substitution, it occurs in the S3 transmembrane helical domain and in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, functional studies demonstrated that V205M markedly alters the activation and deactivation properties of this slow delayed rectifier potassium channel in vitro (Arbour et al., 2008; Eldstrom et al., 2015). Furthermore, the V205M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In summary, V205M in the KCNQ1 gene is interpreted as a pathogenic variant.
Ambry Genetics RCV000252730 SCV000320119 pathogenic Cardiovascular phenotype 2017-04-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000119056 SCV000711083 pathogenic Congenital long QT syndrome 2017-08-07 criteria provided, single submitter clinical testing The p.Val205Met variant in KCNQ1 has been reported in 2 individuals with long QT syndrome and segregated with disease in at least 10 affected relatives from bot h families (Arbour 2008). Additionally, four individuals have been reported to b e homozygous for this variant and present with a clinically more severe phenotyp e that did not include hearing loss (Jackson 2014). This variant has also been r eported by other clinical laboratories in ClinVar (variation ID: 3725) and has b een identified in 1/126300 European chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs151344631). In vitro func tional studies provide evidence that the p.Val205Met variant may impact protein function (Arbour 2008, Eldstrom 2010, Eldstrom 2015). In summary, this variant m eets criteria to be classified as pathogenic for long QT syndrome in an autosoma l dominant manner based upon segregation studies and functional evidence.
Integrated Genetics/Laboratory Corporation of America RCV000148547 SCV000917563 pathogenic Long QT syndrome 2018-07-31 criteria provided, single submitter clinical testing Variant summary: KCNQ1 c.613G>A (p.Val205Met) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 276590 control chromosomes. c.613G>A has been reported in the literature in multiple heterozygous individuals of whom several were affected with Long QT syndrome, as well as in four homozygous patients presenting with a more severe cardiac phenotype, and occasionally with symptoms suggestive of Jervell and Lange-Nielsen syndrome (Jackson 2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Arbour 2008). The most pronounced variant effect results in approximately 30%-50% of the normal channel activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000030815 SCV000053486 pathogenic Long QT syndrome 1 2008-07-01 no assertion criteria provided literature only
Community Genetics, University of British Columbia RCV000057723 SCV000089040 not provided not provided no assertion provided not provided
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000119056 SCV000089242 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:18580685;PMID:20421371;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington RCV000148547 SCV000190260 pathogenic Long QT syndrome 2014-06-01 no assertion criteria provided research

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