rs120074179

Positions:

• chr11-2572089-G-A
• chr11-2572089-G-C
• chr11-2572089-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.760G>A​(p.Val254Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V254L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.58

Genes affected

KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 12) in uniprot entity KCNQ1_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2572089-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 11-2572089-G-A is Pathogenic according to our data. Variant chr11-2572089-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572089-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.760G>A	p.Val254Met	missense_variant	5/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.760G>A	p.Val254Met	missense_variant	5/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.379G>A	p.Val127Met	missense_variant	5/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.499G>A	p.Val167Met	missense_variant	6/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.478-11346G>A		intron_variant				ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460076 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726386

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 06, 2022	PP1_very_strong, PP3, PM1, PM2_supporting, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2023	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) -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 31, 2013	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 S -

Long QT syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Gain of function variants result exclusively in short QT syndrome (MIM#609621), while dominant negative and loss of function variants can cause long QT syndrome (LQTS, MIM#192500), atrial fibrillation (MIM#607554) and Jervell and Lange-Nielsen syndrome (JLNS, MIM#220400) (OMIM, PMIDs: 19632626, 28438721). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. JLNS is characterized by congenital, bilateral deafness and variable degrees of QT prolongation, and is the only condition caused by biallelic variants (PMID: 28438721). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ion transport C-loop domain (Decipher, PMID: 22456477). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least twenty individuals with prolonged QT (PMIDs: 22456477, 29439887). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate in multiple families with prolonged QT (PMID: 29439887). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The p.V254M mutant construct transfected into HEK293T cells demonstrated impaired response to forskolin and a dominant-negative effect when co-transfected with the WT construct, compared to WT only cells (PMID: 22456477). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -

Long QT syndrome Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Medical Research Institute, Tokyo Medical and Dental University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	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. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2018

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. -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	.;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.97, 0.95
MutPred		0.90		.;Loss of helix (P = 0.0376);.;
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.90
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs120074179; hg19: chr11-2593319; COSMIC: COSV50102167;