rs199472707

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000218.3(KCNQ1):​c.677C>T​(p.Ala226Val) 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

KCNQ1
NM_000218.3 missense

Scores

11
6
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3O:1

Conservation

PhyloP100: 7.47
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a helix (size 12) in uniprot entity KCNQ1_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000218.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNQ1NM_000218.3 linkc.677C>T p.Ala226Val missense_variant 4/16 ENST00000155840.12 NP_000209.2 P51787-1Q96AI9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNQ1ENST00000155840.12 linkc.677C>T p.Ala226Val missense_variant 4/161 NM_000218.3 ENSP00000155840.2 P51787-1
KCNQ1ENST00000335475.6 linkc.296C>T p.Ala99Val missense_variant 4/161 ENSP00000334497.5 P51787-2
KCNQ1ENST00000496887.7 linkc.416C>T p.Ala139Val missense_variant 5/165 ENSP00000434560.2 E9PPZ0
KCNQ1ENST00000646564.2 linkc.478-12038C>T intron_variant ENSP00000495806.2 A0A2R8YEQ9

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Long QT syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 16, 2023This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 226 of the KCNQ1 protein (p.Ala226Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 15234419, 24606995; Invitae). ClinVar contains an entry for this variant (Variation ID: 67097). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthMar 05, 2024- -
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 02, 2022The p.A226V variant (also known as c.677C>T), located in coding exon 4 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 677. The alanine at codon 226 is replaced by valine, an amino acid with similar properties. This alteration has been detected in several individuals with long QT syndrome (LQTS) (Shimizu W et al. J. Am. Coll. Cardiol., 2004 Jul;44:117-25; Horigome H et al. Circ Arrhythm Electrophysiol, 2011 Aug;4:456-64; Jons C et al. J. Cardiovasc. Electrophysiol., 2009 Aug;20:859-65; Christiansen M et al. BMC Med. Genet., 2014 Mar;15:31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 01, 2017A variant of uncertain significance has been identified in the KCNQ1 gene. The A226V variant has been reported in association with LQTS (Moss et al., 2007); however, additional clinical information was not provided. Additionally, this variant has been reported in patients with fetal arrhythmia who did not have a definitive diagnosis of LQTS (Mitchell et al., 2012; Cuneo et al., 2013). The A226V variant is not observed in large population cohorts (Lek et al., 2016). Located in the voltage sensor S4 domain, this substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the A226V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. -
Congenital long QT syndrome Other:1
not provided, no classification providedliterature onlyCardiovascular 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:17470695). 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
Uncertain
0.50
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.49
CADD
Uncertain
26
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.97
.;D;.
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Pathogenic
0.83
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.1
.;L;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-3.9
D;D;D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0040
D;D;D
Sift4G
Uncertain
0.026
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.95, 0.91
MutPred
0.85
.;Loss of sheet (P = 0.0063);.;
MVP
0.98
MPC
1.2
ClinPred
0.99
D
GERP RS
4.3
Varity_R
0.74
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199472707; hg19: chr11-2592627; COSMIC: COSV50129661; API