rs199472763

Positions:

• chr11-2583544-C-A
• chr11-2583544-C-G
• chr11-2583544-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.1031C>A​(p.Ala344Glu) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A344G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 NM_000218.3 missense, splice_region
• Scores: Splicing: ADA: 0.6763
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1 O:1
• Conservation: PhyloP100: 7.38

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 hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 chr11-2583544-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 52936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 11-2583544-C-A is Pathogenic according to our data. Variant chr11-2583544-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2583544-C-A is described in Lovd as [Pathogenic]. Variant chr11-2583544-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.1031C>A	p.Ala344Glu	missense_variant, splice_region_variant	7/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1031C>A	p.Ala344Glu	missense_variant, splice_region_variant	7/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.650C>A	p.Ala217Glu	missense_variant, splice_region_variant	7/16	1
KCNQ1	ENST00000496887.7	c.770C>A	p.Ala257Glu	missense_variant, splice_region_variant	8/16	5
KCNQ1	ENST00000646564.2	c.587C>A	p.Ala196Glu	missense_variant, splice_region_variant	3/11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455418 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724374

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/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala344 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9386136, 16922724, 17088455, 17470695, 19490272, 24217263). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 67006). This missense change has been observed in individuals with long QT syndrome (PMID: 15234419, 15840476, 19261104, 21511995, 23098067). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 344 of the KCNQ1 protein (p.Ala344Glu). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2017

The p.A344E variant (also known as c.1031C>A), located in coding exon 7 of the KCNQ1 gene, results from a C to A substitution at nucleotide position 1031. The alanine at codon 344 is replaced by glutamic acid, an amino acid with dissimilar properties, and is located in the S6 region of the KCNQ1 protein. This alteration has been reported in a number of long QT syndrome (LQTS) cohorts (Shimizu W et al. J. Am. Coll. Cardiol. 2004;44:117-25; Tester DJ et al. Heart Rhythm. 2005;2:507-17; Yasuda K et al. Pediatr Int. 2008;50:611-4; Horigome H et al. Circ Arrhythm Electrophysiol. 2011;4:456-64; Stattin EL et al. BMC Cardiovasc Disord. 2012;12:95; Miyazaki A et al. JACC:Clinical Electrophysiology. 2016;2(3):266-76). In one study, an RNA assay indicated that this alteration leads to a splicing defect (Itoh H et al. Eur. J. Hum. Genet. 2016;24:1160-6). Multiple alterations in the same codon (c.1031C>T p.A344V, c.1031C>G p.A344G, c.1032G>C p.A344A, c.1032G>T p.A344A, and c.1032G>T p.A344A) have been associated with LQTS (Donger C et al. Circulation. 1997;96:2778-81; Kanters JK et al. J. Cardiovasc. Electrophysiol.1998;9:620-4; Murray A e tal. Circulation. 1999;100(10):1077-84; Burns C et al. J Arrhythm. 2016;32:456-461). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jul 22, 2014

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.Ala344Glu Given small amount of case data and absence of segregation data, we consider this variant of uncertain significance, probably disease causing. The variant has been seen in at least 2 unrelated cases of long QT syndrome with no segregation data. This variant is located in a non-pore region of the gene in exon 7. Shimizu W et al. (2004) reported this variant in one family with long QT syndrome. Specific phenotype data for this family was not given. The study population was 37 unrelated Japanese LQT1 families. Tester D et al. (2005) reported this variant in one family with long QT in their compendium. This cohort is 541 individuals referred to Mayo Clinic's Sudden Death Genomic Clinic (Ackerman) who underwent testing for variants in KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6) between August 1997 and July 2004. No specific phenotype data was given for this family. It should be noted that the authors state that regardless of the clinical diagnostic score for LQTS (“Schwartz score”), a sample was accepted for genetic testing if the referring physician had made a tentative clinical diagnosis of LQTS. The authors note that be considered as a probable pathogenic LQTS causing variant, the nonsynonymous variant must have been absent in all published databases of channel polymorphisms and their previous comprehensive analysis of 1,488 reference alleles. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 344 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (Ala344Val, which we classify as very likely disease causing) and nearby codons (p.Pro343Arg; p.Pro343Ser; p.Pro343Lys; p.G345Arg; p.G345E). In total the variant has not been seen in ~7,244 published controls and individuals from publicly available population datasets. There is no variation at codon 344 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 2/7/14). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 2/7/14). The variant was not observed in the following published control samples: Tester et al did not report this variant in 744 control individuals Sequencing of individuals from the general population has shown that 8-10% of all individuals have a rare or novel variant in one of the long QT genes included in this test (Kapa et al 2009, Callis et al 2012). Thus when we find a novel variant in a long QT gene it could either be a causative variant or one of the many benign unique variants we all have. -

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:15234419;PMID:15840476). 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	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	D;T;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.7	D;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.0020	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.93		Loss of glycosylation at S349 (P = 0.2465);.;.;
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.68
dbscSNV1_RF	Benign	0.68
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: rs199472763; hg19: chr11-2604774;