11-2583535-C-T

Position:

• chr11-2583535-C-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.1022C>T​(p.Ala341Val) 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. A341E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 7.42

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 helix (size 19) in uniprot entity KCNQ1_HUMAN there are 35 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 chr11-2583535-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 11-2583535-C-T is Pathogenic according to our data. Variant chr11-2583535-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2583535-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1022C>T	p.Ala341Val	missense_variant	7/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1022C>T	p.Ala341Val	missense_variant	7/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.641C>T	p.Ala214Val	missense_variant	7/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.761C>T	p.Ala254Val	missense_variant	8/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.578C>T	p.Ala193Val	missense_variant	3/11			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Mar 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.1022C>T (p.Ala341Val) missense variant in KCNQ1 gene has been reported in individuals affected with long QT syndrome (Brink et al., 2005). This variant has been observed to segregate with long QT syndrome (LQTS) in several families (Brink et al., 2005). Experimental studies have shown that this missense change reduces the current of the KCNQ1 channel in a dominant negative fashion (Brink et al., 2005). This variant disrupts the p.Ala341 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in affected individuals (Anastasakis et al., 2006), suggesting that it is a clinically significant residue. The p.Ala341Val variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Ala at position 341 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala341Val in KCNQ1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	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, PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (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 S6 transmembrane domain (PMID: 19716085). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. An alternative change to a glutamic acid and a glycine have been reported in multiple individuals with LQTS (ClinVar, PMID: 19716085). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a South African founder mutation and has multiple pathogenic entries in ClinVar (PMID: 24217263, 19716085). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes	Aug 01, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 25, 2005	- -

not provided Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 05, 2015	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.Ala341Val Given the very strong case and segregation data and absence in general populations samples, we consider this variant very likely disease causing. This variant has been reported in at least 27 unrelated cases with Long QT Syndrome. Wang et al (1996) initially reported 5 families with the p.Ala341Val variant and long QT Syndrome (reported as p.Ala212Val). The variant segregated with disease in 55 affected individuals across the 5 families (Family 1- 6 affected, Family 2- 18 affected, Family 3-18 affected, Family 4- 3 affected and Family 5-2 affected). These families were recruited from North America and Europe. Russell et al (1996) reported monozygotic twins with the variant and LQT. The variant was de novo; neither parent carried it, both parents had normal QT intervals, and paternity was confirmed by molecular analysis. The family for this study was recruited from Michigan and Atlanta. De Jager et al (1996) reported a family of Northern European Afrikaner descent with p.Ala341Val; in this family all the affected individuals shared a common disease associated haplotype thus indicating a founder effect in the South African population. Donger et al (1997) reported a family with 5 affected individuals- 2 had syncope before age 10 and 3 had a SCD before age 40. Li et al (1998) reported p.Ala341Val in 2 out of 115 families from the Int LQT Registry (N. America, Europe , Asia). One of these families can be viewed as additive since they are of Japanese origin and the prior studies only included European and American families. Splawski et al (2000) also reported 7 families with disease and variant but these were previously published cases (Wang, Russell, Donger and Li). Jongbloed et al (2002) identified the variant in 1 out of 32 families of Dutch and Belgian ancestry. Kobori et al (2004) reported 2 families with the variant. Westenskow et al (2004) reported a case with the p.Ala341Val variant in KCNQ1 and an additional variant in KCNE1 (p.P127T). The patients QTc was 530 ms. Tester et al (2005) reported 3 unrelated individuals with the variant out of 541 cases sent for genetic testing in Ackerman’s lab between August 1997 and July 2004. In 2005 Lai et al reported of a case positive for the variant who presented with an “attack” during swimming. Millat et al (2006) reported 2 unrelated cases with the variant: a 9 yo old male (QTc 503ms) with syncope triggered by swimming and a 16yo female (QTc 544 ms) with syncope and torsade de pointes. The variant was reported in 8 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). 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). In 2010, Kotta et al reported the variant in 1 out of 17 unrelated cases with LQT in Greece. This is a semi conservative amino acid change with a nonpolar, neutral Alanine replaced with a non polar neutral Valine. The variant is located in the S6 transmembrane domain of the K+ channel. In silico analysis (SIFT, PolyPhen) predicts the amino acid change to be deleterious to the resulting protein. Missense variants in the same codon and nearby codons (A341E, A341G, L342F, P343L, A344V) have been reported in association with LQTS. The variant is listed in genomemed.org, fsm, and hearing.harvard databases. There are no studies involving mouse models. In total, the variant has not been seen in ~8380 publis -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2024	Identified in numerous patients with LQTS referred for genetic testing at GeneDx and in published literature; reported to be generally severe in clinical expression with patients demonstrating more frequent cardiac events beginning at younger ages compared to the overall LQTS population (PMID: 8528244, 10376919, 12402336, 16246960, 17984373, 22949429, 26118460, 29194874); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a disruption of the normal electrophysiological properties and a non-functional channel (PMID: 15051636, 21854832, 22095730, 24705789, 34505893); 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: 9570196, 29740400, 21810471, 25634836, 10376919, 24705789, 21854832, 24912595, 15051636, 12402336, 22949429, 17984373, 26910742, 26118460, 28003625, 8528244, 29194874, 18308161, 14678125, 16627448, 19841300, 8872472, 8818942, 17470695, 9386136, 16155735, 16922724, 15840476, 15234419, 19716085, 10973849, 29439887, 30898243, 30878014, 31737537, 30847666, 32443288, 36243179, 34546463, 34505893, 32383558, 32470535, 34860437, 16246960, 22095730) -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:8528244;PMID:8818942;PMID:8872472;PMID:9386136;PMID:9570196;PMID:10973849;PMID:12402336;PMID:14678125;PMID:15028050;PMID:15051636;PMID:15840476;PMID:16155735;PMID:16922724;PMID:19716085;PMID:19841300;PMID:21810471;PMID:10376919;PMID:21854832;PMID:15234419;PMID:16246960;PMID:18308161;PMID:17470695;PMID:22095730). -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 28, 2024	PP1_strong, PP3, PM1, PM2, PS3_supporting, PS4 -

Long QT syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Oct 23, 2018	This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 341 of the KCNQ1 protein (p.Ala341Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (LQTS) (PMID: 16246960, 16627448). It is commonly reported in individuals of South African ancestry (PMID: 8528244, 15051636, 16246960, 16627448, 17984373, 22949429, 25634836). ClinVar contains an entry for this variant (Variation ID: 3121). 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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 10376919, 16246960, 21854832, 22095730). This variant disrupts the p.Ala341 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8528244, 10086971, 16627448). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, flagged submission	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 02, 2014	Observed in one patient in Stanford Center for Inherited Cardiovascular Disease with long QT syndrome. Patient underwent genetic testing at GeneDx, which included sequencing and exon-level array analysis of AKAP9, ANK2, CACNA1C, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNQ1, SCN5A, SCN4B, SNTA1. Given the very strong case and segregation data and absence in general population samples, we consider this variant very likely disease causing. This variant has been reported in at least 27 unrelated cases with Long QT syndrome (not including our patient). Wang et al (1996) initially reported 5 families with the p.Ala341Val variant and long QT Syndrome (reported as p.Ala212Val). The variant segregated with disease in 55 affected individuals across the 5 families (Family 1- 6 affected, Family 2- 18 affected, Family 3-18 affected, Family 4- 3 affected and Family 5-2 affected). These families were recruited from North America and Europe. Russell et al (1996) reported monozygotic twins with the variant and LQT. The variant was de novo; neither parent carried it, both parents had normal QT intervals, and paternity was confirmed by molecular analysis. The family for this study was recruited from Michigan and Atlanta. De Jager et al (1996) reported a family of Northern European Afrikaner descent with p.Ala341Val; in this family all the affected individuals shared a common disease associated haplotype thus indicating a founder effect in the South African population. Donger et al (1997) reported a family with 5 affected individuals- 2 had syncope before age 10 and 3 had a SCD before age 40. Li et al (1998) reported p.Ala341Val in 2 out of 115 families from the Int LQT Registry (N. America, Europe , Asia). One of these families can be viewed as additive since they are of Japanese origin and the prior studies only included European and American families. Splawski et al (2000) also reported 7 families with disease and variant but these were previously published cases (Wang, Russell, Donger and Li). Jongbloed et al (2002) identified the variant in 1 out of 32 families of Dutch and Belgian ancestry. Kobori et al (2004) reported 2 families with the variant. Westenskow et al (2004) reported a case with the p.Ala341Val variant in KCNQ1 and an additional variant in KCNE1 (p.P127T). The patients QTc was 530 ms. Tester et al (2005) reported 3 unrelated individuals with the variant out of 541 cases sent for genetic testing in Ackerman’s lab between August 1997 and July 2004. In 2005 Lai et al reported of a case positive for the variant who presented with an “attack” during swimming. Millat et al (2006) reported 2 unrelated cases with the variant: a 9 yo old male (QTc 503ms) with syncope triggered by swimming and a 16yo female (QTc 544 ms) with syncope and torsade de pointes. The variant was reported in 8 individuals in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). This may include our patient, given the timing. 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). In 2010, Kotta et al reported the variant in 1 out of 17 unrelated cases with LQT in Greece. This is a semi conservative amino acid change with a nonpolar, neutral Alanine replaced with a non polar neutral Valine. The variant is located in the S6 transmembrane domain of the K+ channel. In silico analysis (SIFT, PolyPhen) predicts the amino acid change to be deleterious to the resulting protein. Missense variants in the same codon and nearby codons (A341E, A341G, L342F, P343L, A344V) have been reported in association with LQTS. The variant is listed in genomemed.org, fsm, and hearing.harvard databases. There are no studies involving mouse models. In total, -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2022

The p.A341V pathogenic mutation (also known as c.1022C>T), located in coding exon 7 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 1022. The alanine at codon 341 is replaced by valine, an amino acid with similar properties. This alteration (historically described as A212V) has been reported as de novo in a family with monozygotic twins with long QT syndrome (LQTS) (Russell MW et al. Hum. Mol. Genet., 1996 Sep;5:1319-24). In addition, this variant has been reported in numerous individuals and families with LQTS, including reports as a founder mutation associated with severe phenotype in a large South African cohort (Anastasakis A et al. Europace, 2006 Apr;8:241-4; Crotti L et al. Circulation, 2007 Nov;116:2366-75; Wang Q et al. Nat. Genet., 1996 Jan;12:17-23). Additional alterations at this CpG dinucleotide position and in nearby amino acids have also been reported association with LQTS, leading researchers to consider this as a hot spot region (Wang Q et al. Nat. Genet., 1996 Jan;12:17-23; Russell MW et al. Hum. Mol. Genet., 1996 Sep;5:1319-24; Crotti L et al. Circulation, 2007 Nov;116:2366-75). Functional studies demonstrated a defective protein producing little or no activating potassium channel current, thereby causing a pronounced prolongation of repolarization (Mikuni I et al. Biochim. Biophys. Acta, 2011 Dec;1810:1285-93; Heijman J et al. Circ. Res., 2012 Jan;110:211-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.6	D;.;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.0060	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.95		Loss of catalytic residue at A341 (P = 0.3542);.;.;
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.93
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12720459; hg19: chr11-2604765; COSMIC: COSV50102956;