Submissions for variant NM_000218.3(KCNQ1):c.760G>A (p.Val254Met)

dbSNP: rs120074179

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000190212	SCV000074131	pathogenic	Long QT syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 254 of the KCNQ1 protein (p.Val254Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 8528244, 9386136, 10973849, 12820704, 15234419, 15466642, 15840476, 17470695, 19716085). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Val125Met. ClinVar contains an entry for this variant (Variation ID: 3118). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 10376919, 22456477). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000182109	SCV000234412	pathogenic	not provided	2023-08-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a dominant negative effect on channel function (Wang et al., 1999; Barsheshet et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31737537, 22949429, 15466642, 34505893, 32581825, 14756674, 8528244, 26743238, 25854863, 9386136, 12820704, 29439887, 28012188, 22456477, 28988457, 32936022, 32015334, 10376919, 37124559, 33504163)
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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000182109	SCV004226839	pathogenic	not provided	2022-12-06	criteria provided, single submitter	clinical testing	PP1_very_strong, PP3, PM1, PM2_supporting, PS4
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).