rs199473399

Variant summary

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

The NM_000218.3(KCNQ1):ā€‹c.560T>Cā€‹(p.Leu187Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,180 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: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

6
5
8

Clinical Significance

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

Conservation

PhyloP100: 5.84
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a helix (size 6) in uniprot entity KCNQ1_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000218.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.971
PP5
Variant 11-2570710-T-C is Pathogenic according to our data. Variant chr11-2570710-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53066.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=2, not_provided=1}. Variant chr11-2570710-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNQ1NM_000218.3 linkc.560T>C p.Leu187Pro missense_variant 3/16 ENST00000155840.12 NP_000209.2 P51787-1Q96AI9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNQ1ENST00000155840.12 linkc.560T>C p.Leu187Pro missense_variant 3/161 NM_000218.3 ENSP00000155840.2 P51787-1
KCNQ1ENST00000335475.6 linkc.179T>C p.Leu60Pro missense_variant 3/161 ENSP00000334497.5 P51787-2
KCNQ1ENST00000496887.7 linkc.299T>C p.Leu100Pro missense_variant 4/165 ENSP00000434560.2 E9PPZ0
KCNQ1ENST00000646564.2 linkc.478-12725T>C intron_variant ENSP00000495806.2 A0A2R8YEQ9

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000801
AC:
2
AN:
249636
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135358
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460180
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726478
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Laboratory - Cardiogenetics, CHU de NantesAug 01, 2023- -
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2025This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 187 of the KCNQ1 protein (p.Leu187Pro). This variant is present in population databases (rs199473399, gnomAD 0.002%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 18808722, 23631430). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53066). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNQ1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNQ1 function (PMID: 30571187, 32797034). For these reasons, this variant has been classified as Pathogenic. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 24, 2023Identified in an individual suspected of having long QT syndrome, however specific clinical information was not provided (Lieve et al., 2013); Identified in several individuals with long QT syndrome in a large family, however the variant was also seen in several family members with an uncertain long QT syndrome diagnosis and in one unaffected family member making it unclear if the variant is segregating with disease in the family (Zhang et al., 2008); 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; This variant is associated with the following publications: (PMID: 23631430, 30571187, 18808722) -
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 12, 2018The c.560T>C (p.L187P) alteration is located in exon 3 (coding exon 3) of the KCNQ1 gene. This alteration results from a T to C substitution at nucleotide position 560, causing the leucine (L) at amino acid position 187 to be replaced by a proline (P). 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:18808722). 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
Benign
0.21
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.44
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
.;D;.
Eigen
Benign
0.027
Eigen_PC
Benign
0.13
FATHMM_MKL
Benign
0.60
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
0.88
D
MutationAssessor
Benign
1.9
.;L;.
PrimateAI
Uncertain
0.59
T
PROVEAN
Uncertain
-4.2
D;D;D
REVEL
Pathogenic
0.77
Sift
Benign
0.18
T;D;D
Sift4G
Benign
0.33
T;T;T
Polyphen
0.047
.;B;.
Vest4
0.90, 0.81
MutPred
0.92
.;Loss of stability (P = 0.0531);.;
MVP
0.96
MPC
0.63
ClinPred
0.82
D
GERP RS
4.4
Varity_R
0.88
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs199473399; hg19: chr11-2591940; API