rs199473399
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000218.3(KCNQ1):āc.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
NM_000218.3 missense
Scores
6
5
8
Clinical Significance
Conservation
PhyloP100: 5.84
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 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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.560T>C | p.Leu187Pro | missense_variant | 3/16 | 1 | NM_000218.3 | ENSP00000155840.2 | ||
KCNQ1 | ENST00000335475.6 | c.179T>C | p.Leu60Pro | missense_variant | 3/16 | 1 | ENSP00000334497.5 | |||
KCNQ1 | ENST00000496887.7 | c.299T>C | p.Leu100Pro | missense_variant | 4/16 | 5 | ENSP00000434560.2 | |||
KCNQ1 | ENST00000646564.2 | c.478-12725T>C | intron_variant | ENSP00000495806.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249636Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135358
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460180Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726478
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GnomAD4 genome Cov.: 33
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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 submitter | clinical testing | Molecular Genetics Laboratory - Cardiogenetics, CHU de Nantes | Aug 01, 2023 | - - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2025 | This 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 submitter | clinical testing | GeneDx | Feb 24, 2023 | Identified 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 submitter | clinical testing | Ambry Genetics | Feb 12, 2018 | The 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 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: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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
.;D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
.;L;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Benign
T;D;D
Sift4G
Benign
T;T;T
Polyphen
0.047
.;B;.
Vest4
0.90, 0.81
MutPred
0.92
.;Loss of stability (P = 0.0531);.;
MVP
MPC
0.63
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at