rs199473399

Positions:

Variant summary

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

The NM_000218.3(KCNQ1):c.560T>C(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 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

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]

KCNQ1 links:

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
KCNQ1	NM_000218.3 link	c.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	UniProt
KCNQ1	ENST00000155840.12 link	c.560T>C	p.Leu187Pro	missense_variant	3/16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6 link	c.179T>C	p.Leu60Pro	missense_variant	3/16	1		ENSP00000334497.5	P51787-2
KCNQ1	ENST00000496887.7 link	c.299T>C	p.Leu100Pro	missense_variant	4/16	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 link	c.478-12725T>C		intron_variant				ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000801

AC:

AN:

249636

Hom.:

AF XY:

0.00000739

AC XY:

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:

AN:

1460180

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

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.:

ExAC

AF:

0.00000824

AC:

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 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

.;D;.

Eigen

Benign

0.027

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Benign

1.9

.;L;.

PrimateAI

Uncertain

0.59

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over