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rs199473451

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000218.3(KCNQ1):c.430A>G(p.Thr144Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 34)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

8
9
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2O:1

Conservation

PhyloP100: 5.78
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 9 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000218.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.966
PP5
Variant 11-2527971-A-G is Pathogenic according to our data. Variant chr11-2527971-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67073.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic=1, Uncertain_significance=2}. Variant chr11-2527971-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNQ1NM_000218.3 linkuse as main transcriptc.430A>G p.Thr144Ala missense_variant 2/16 ENST00000155840.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNQ1ENST00000155840.12 linkuse as main transcriptc.430A>G p.Thr144Ala missense_variant 2/161 NM_000218.3 P1P51787-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461786
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727202
show subpopulations
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 18, 2023This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 144 of the KCNQ1 protein (p.Thr144Ala). 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: 14678125, 17470695). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67073). 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: 23271449, 30571187). For these reasons, this variant has been classified as Pathogenic. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 13, 2022Reported independently and in conjunction with the p.(R594P) variant in the KCNQ1 gene in multiple unrelated individuals with LQTS (Zareba et al., 2003; Miller et al., 2007; Moss et al., 2007; Kapplinger et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies demonstrated the p.(T144A) variant resulted in decreased potassium currents with slowed activation, accelerated deactivation kinetics, and/or a depolarizing shift in the voltage dependence of activation when expressed in homologous potassium channel genes (KCNQ2/3) (Full et al., 2013; Vanoye et al., 2018); Reported in ClinVar (ClinVar Variant ID# 67073; ClinVar); This variant is associated with the following publications: (PMID: 26734131, 21152909, 19716085, 17470695, 17224687, 22581653, 30571187, 23271449, 14678125) -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 13, 2022The c.430A>G (p.T144A) alteration is located in exon 2 (coding exon 2) of the KCNQ1 gene. This alteration results from a A to G substitution at nucleotide position 430, causing the threonine (T) at amino acid position 144 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
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:14678125;PMID:17224687;PMID:19716085;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
Pathogenic
0.91
CardioboostArm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
Cadd
Pathogenic
26
Dann
Uncertain
1.0
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Uncertain
0.90
D;D;D;D;.
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Uncertain
-4.2
D;D;.;D;D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0030
D;D;.;D;.
Sift4G
Uncertain
0.0020
D;D;.;D;D
Polyphen
1.0
.;D;.;.;.
Vest4
0.97, 0.93
MutPred
0.84
.;Loss of glycosylation at T144 (P = 0.0865);.;.;.;
MVP
0.98
MPC
2.1
ClinPred
0.99
D
GERP RS
3.2
Varity_R
0.85
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: rs199473451; hg19: chr11-2549201; API