ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.379G>A (p.Val127Met) (rs120074179)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000190212 SCV000074131 pathogenic Long QT syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 254 of the KCNQ1 protein (p.Val254Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (rs120074179, ExAC no frequency). This variant has been demonstrated to strongly segregate with the long QT phenotype in a very large family (PMID: 8528244) and has been observed in numerous additional families and unrelated cases with long QT syndrome (PMID: 9386136, 10973849, 12820704, 15234419, 15466642, 15840476, 17470695, 19716085). This variant is also known as p.Val125Met in the literature. ClinVar contains an entry for this variant (Variation ID: 3118). Several experimental studies have shown that this missense change has a dominant-negative effect in vitro (PMID: 10376919, 22456477). In summary, this variant is absent from controls, has shown strong segregation with long QT syndrome, has been observed in many unrelated individuals with long QT syndrome, and has been demonstrated to have a functional effect. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000182109 SCV000234412 pathogenic not provided 2020-09-24 criteria provided, single submitter clinical testing Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 3118; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Published functional studies suggest a dominant negative effect on channel function (Wang et al., 1999; Barsheshet et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31737537, 22949429, 15466642, 10376919, 32581825, 14756674, 8528244, 26743238, 25854863, 9386136, 12820704, 29439887, 28012188, 22456477, 28988457, 32936022, 32015334)
Ambry Genetics RCV000619506 SCV000737811 pathogenic Cardiovascular phenotype 2018-12-31 criteria provided, single submitter clinical testing The p.V254M pathogenic mutation (also known as c.760G>A), located in coding exon 5 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 760. The valine at codon 254 is replaced by methionine, an amino acid with highly similar properties. This alteration has been described in numerous patients with long QT syndrome, and the mutation segregated with disease in multiple individuals from several different families (Wang Q et al. Nat Genet. 1996;12(1):17-23; Yagi N et al. J Cardiol, 2018 Jul;72:56-65). In functional in vitro analyses, this alteration adversely affected the voltage-gated potassium ion channel, resulting in decreased current amplitude and prolongation of the channel activation threshold (Wang Z et al. J Cardiovasc Electrophysiol. 1999;10(6):817-26). Based on the supporting evidence, p.V254M is interpreted as a disease-causing mutation.
OMIM RCV000003265 SCV000023423 pathogenic Long QT syndrome 1 1996-01-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057749 SCV000089268 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:8528244;PMID:9386136;PMID:10973849;PMID:12820704;PMID:14678125;PMID:14756674;PMID:15466642;PMID:15840476;PMID:16937190;PMID:19716085;PMID:19841300;PMID:10376919;PMID:15234419;PMID:17470695;PMID:22456477). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Medical Research Institute,Tokyo Medical and Dental University RCV000190212 SCV000222063 likely pathogenic Long QT syndrome no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000182109 SCV000280162 pathogenic not provided 2013-12-31 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Val254Met Based on the data reviewed below, we classify this variant as very likely disease causing. This variant has been reported in at least 23 unrelated cases with Long QT Syndrome to date. There is strong segregation data on the variant. The variant has also been reported as p.Val125Met (using an old numbering system). Wang et al (1996) initially reported the variant in a large family with LQTS from Utah segregating with disease in 70 individuals (reported as p.Val125Met). This was actually the family that led to the initial identification of KCNQ1 as the first long QT gene. Donger et al (1997) reported the variant in 1 out of 20 families with LQT recruited in France. Within this family there were 11 carriers, 3 who had an initial syncopal event before age 10 and 4 who had a sudden cardiac death before age 40. Splawski et al (2000) observed the variant in 2 families. In 2003 Paulussen et al reported a family from Belgium with p.Val254Met in KCNQ1 and p.Ala572Asp in SCN5A and long QT syndrome and sudden death. The proband was an 11 year old boy with a personal history of syncope and a QTc of 483 ms at rest. Zareba et al (2003) include 70 patients with this variant from the international long QT registry in a study on genotype-phenotype correlation (likely overlaps with prior reports including Wang et al). In a paper from Ackerman’s group on channel defects in arrhythmias associated with swimming, Choi et al (2004) reported this variant 2 out of 388 unrelated individuals sent for genetic testing between August 1997 to May 2003. Tester et al (2005) also reported 2 unrelated cases analyzed by Ackerman’s group and these cases are very likely the same as those reported by Choi et al. Shimizu et al (2004) observed the variant in 2 unrelated long QT patients in their Japanese cohort. In a study on T-wave morphology in long QT Struijk et al (2006) report one family with this variant and long QT syndrome in their Danish cohort. The variant was reported in 10 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Those cases likely overlap with the data in Kapa et al (2009) and Giudicessi et al (2012) since these are all from Ackerman's group and use data from his cohort and from the Familion cohort. Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Wedekind et al (2004) describe a family with long QT and sudden death from their German cohort with p.Val254Met in cis with p.Val417Met. In a genotype-phenotype study Barsheshet et al (2012) report on 62 individuals with the variant and disease recruited from the International LQT Registry (Rochester, Netherlands, Japanese, Danish and Swedish populations), which very likely overlap prior reports. Crotti et al (2012) also report 1 case out of 169 individuals obtained from a database in Pavia. This case appears to be distinct from other reports. Hedley et al (2013) report 1 out of 21 unrelated cases in South Africa with the variant and long QT. Moss et al (2007) include this variant in a study on genotype-phenotype correlations, however that sample was drawn from the international registry, the Dutch registry, and the Japanese registry, so these cases likely overlap with prior reports. This is a conservative amino acid change with a nonpolar, neutral Valine replaced with a nonpolar, neutral Methionine. The variant is located in the S4/5 cytoplasmic domain of the Potassioum channel. In silico analysis predicts the amino acid change to be deleterious to the resulting protein (SIFT, PolyPhen2). Missense variants at the same codon (p.Val254Leu) in nearby codons (p.Gly245Val, p.Trp248Cys, p.Trp248Arg, p.Leu250His, p.Leu250Pro, p.Leu251Pro, p.His258Asn, p.His258Pro, p.His258Arg, p.Arg259Cys, p.Arg259His, p.Arg259Leu, p.Glu261Asp, p.Glu261Lys, p.Glu261Gln, p.Leu262Val) have been reported in association with LQTS. We could find no functional studies involving mouse models. In total the variant has not been seen in 8290 published controls and publicly available general population samples. The variant was not observed in a total of 1790 published controls. Wang et al (1996) did not observe the variant in more than 200 control individuals (likely same controls reported by Splawski et al (2000) because from the same research group). Paulussen et al (2003) report that the variant was absent in 90 Caucasian controls. Donger et al (1997) did not observe the variant in 100 control individuals. Wedekind et al (2004) indicate that the variant was absent in 100 presumably healthy controls of unspecified race. Kapplinger et al (2009) report that p.Val254Met was not observed in 1300 presumably healthy controls (47% Caucasian, 26% African American, 11% Hispanic, 10% Asian, and 6% unknown/other). The variant is listed in 1000Genomes with rs2608813, however inputting this rs number in dbSNP results in an error message. There is no variation at codon 254 in the NHLBI ESP, which currently includes calls on ~6500 individuals (as of January 9th 2014).

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