NM_000218.3:c.817C>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000218.3(KCNQ1):c.817C>T(p.Leu273Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,448 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L273R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 3.04

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 Pathogenic. Variant got 16 ACMG points.

PM1

In a helix (size 25) in uniprot entity KCNQ1_HUMAN there are 38 pathogenic changes around while only 0 benign (100%) in NM_000218.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2572883-T-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

PP5

Variant 11-2572882-C-T is Pathogenic according to our data. Variant chr11-2572882-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572882-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3 link	c.817C>T	p.Leu273Phe	missense_variant	Exon 6 of 16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KCNQ1	ENST00000155840.12 link	c.817C>T	p.Leu273Phe	missense_variant	Exon 6 of 16	1	NM_000218.3	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6 link	c.436C>T	p.Leu146Phe	missense_variant	Exon 6 of 16	1		ENSP00000334497.5	P51787-2
KCNQ1	ENST00000496887.7 link	c.556C>T	p.Leu186Phe	missense_variant	Exon 7 of 16	5		ENSP00000434560.2	E9PPZ0
KCNQ1	ENST00000646564.2 link	c.478-10553C>T		intron_variant	Intron 2 of 10			ENSP00000495806.2	A0A2R8YEQ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250444

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135696

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461448

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727040

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:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:3

Jul 21, 2023

deCODE genetics, Amgen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The variant NM_000218.3:c.817C>T (chr11:2572882) in KCNQ1 was detected in 40 heterozygotes out of 58K WGS Icelanders (MAF= 0,034%). Following imputation in a set of 166K Icelanders (120 imputed heterozygotes) we observed an association with an elongation of the qt interval on ECG using measurements from 80068 individuals (Effect (SD)= 1.71, P= 1.67e-35) and sudden cardiac death using 4784 cases and 358521 controls (OR= 3.17, P= 5.78e-03). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PS4, PM1, PP3, PP5_Strong) this variant classifies as pathogenic. -

Jan 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Apr 14, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect as this variant significantly alters potassium ion channel function (Shalaby et al., 1997; Seebohm et al., 2001; Peretz 2002; Gibor et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28438721, 27064559, 15840476, 11216980, 11278406, 17704175, 12482884, 11530100, 15935335, 21964171, 8528244, 24372464, 25645639, 22949429, 28249770, 10973849, 14678125, 16922724, 17470695, 19716085, 15649981, 22581653, 19841300, 31737537, 26582918, 9323054, 33087929, 27535533) -

Jul 30, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP3, PM2, PM3_supporting, PS3, PS4 -

Long QT syndrome

Pathogenic:2

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 273 of the KCNQ1 protein (p.Leu273Phe). This variant is present in population databases (rs120074180, gnomAD 0.0009%). This missense change has been observed in individuals with Jervell and Lange-Nielsen syndrome and long QT syndrome with or without left ventricular non-compaction cardiomyopathy and epilepsy (PMID: 8528244, 10973849, 16922724, 22949429, 24372464, 24606995, 25645639, 28249770). It has also been observed to segregate with disease in related individuals. This variant is also known as L272F and L144F. ClinVar contains an entry for this variant (Variation ID: 3119). 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) 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: 9323054, 11278406, 15935335). For these reasons, this variant has been classified as Pathogenic. -

Feb 05, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNQ1 c.817C>T (p.Leu273Phe) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250444 control chromosomes. c.817C>T has been reported in the literature in multiple individuals and families affected with Long QT Syndrome (Kharbanda_2017, Wang_1996, Burns_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. This report shows that the variant displays a pronounced KCNQ1 inactivation (Seebohm_2001). The following publications have been ascertained in the context of this evaluation (PMID: 27920829, 28249770, 11278406, 8528244). ClinVar contains an entry for this variant (Variation ID: 3119). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Apr 29, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L273F pathogenic mutation (also known as c.817C>T), located in coding exon 6 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 817. The leucine at codon 273 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in subjects with long QT syndrome and Jervell and Lange-Nielsen syndrome and has shown strong segregation with disease (Wang Q et al. Nat. Genet., 1996 Jan;12:17-23; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Tiron C et al. Seizure, 2015 Feb;25:65-7; Al-Aama JY et al. Clin. Genet., 2015 Dec;87:74-9). In addition, this alteration was shown to have an impact on protein function (Shalaby FY et al. Circulation, 1997 Sep;96:1733-6; Seebohm G et al. J. Biol. Chem., 2001 Apr;276:13600-5; Wilson AJ et al. Cardiovasc. Res., 2005 Aug;67:476-86). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Congenital long QT syndrome

Other:1

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:8528244;PMID:9323054;PMID:10973849;PMID:11216980;PMID:14678125;PMID:15840476;PMID:16922724;PMID:16937190;PMID:19716085;PMID:19841300;PMID:17470695;PMID:15935335;PMID:11278406). 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

0.98

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

.;D;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.79

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

.;M;.

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.9

D;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.94, 0.90

MutPred

0.81

.;Loss of stability (P = 0.2507);.;

MVP

0.98

MPC

1.2

ClinPred

0.99

GERP RS

3.7

Varity_R

0.98

gMVP

0.97

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.

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