chr11-2571391-C-T

Position:

chr11-2571391-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PP3PP5_Very_Strong

The NM_000218.3(KCNQ1):c.671C>T(p.Thr224Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,611,626 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 5.66

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 11 ACMG points.

PM1

In a helix (size 12) in uniprot entity KCNQ1_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000218.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

PP5

Variant 11-2571391-C-T is Pathogenic according to our data. Variant chr11-2571391-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2571391-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.671C>T	p.Thr224Met	missense_variant	4/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.671C>T	p.Thr224Met	missense_variant	4/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.290C>T	p.Thr97Met	missense_variant	4/16	1		ENSP00000334497		P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.410C>T	p.Thr137Met	missense_variant	5/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.478-12044C>T		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0165

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248566

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134924

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:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1459502

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726174

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000869

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Translational Genomics Laboratory, University of Maryland School of Medicine	Dec 21, 2017	The c.671C>T variant in codon 224 (exon 5) of the potassium voltage-gated channel subfamily Q member 1 gene, KCNQ1, results in the substitution of Threonine to Methionine. Missense variants in the KCNQ1 gene are known to cause autosomal dominant hereditary long QT syndrome 1 (also known as Romano-Ward syndrome) and autosomal recessive Jervell and Lange-Nielsen syndrome (24667783, 15840476, 27761162). The c.671C>T variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases, however the c.671C>T variant was previously reported in a patient with long QT syndrome (19716085 Multiple lines of computational evidence (MutationTaster, FATHMM, GERP, MetaSVM, MetalR, Provean, LRT, SIFT) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. The c.671C>T variant is located within a transmembrane region of the protein that has minimal benign variation among individuals in population databases and in the literature (27761162, 17227916). ACMG criteria = PS4, PM1, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 224 of the KCNQ1 protein (p.Thr224Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with long QT syndrome (PMID: 19841298, 33141630; external communication). It is commonly reported in individuals of Amish ancestry (PMID: 19841298; external communication). ClinVar contains an entry for this variant (Variation ID: 67096). 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: 33141630). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 18, 2024	Variant summary: KCNQ1 c.671C>T (p.Thr224Met) results in a non-conservative amino acid change in 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 248566 control chromosomes (gnomAD). c.671C>T has been reported in the literature in individuals affected with Long QT Syndrome (e.g. Mahdieh_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a loss of channel function (Streeten_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32470535, 33141630). ClinVar contains an entry for this variant (Variation ID: 67096). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2024	Reported as highly enriched in the Amish (carrier frequency 1/45), likely through a founder effect and genetic drift (PMID: 33141630); Reported in >20 individuals with LQTS, either of Amish lineage or unspecified, however, segregation data were not described and it is unclear how many individuals are from the same kindred (PMID: 19716085, 19841298, 28794082, 34319147); Published functional studies showed that p.(T224M) generates significantly less current than wild type channel; additional studies are warranted to validate the functional effect of this variant in vivo (PMID: 33141630); 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: 22581653, 19841298, 34467620, 34532947, 28794082, 34319147, 34505893, 32470535, 24223155, 33141630, 19716085) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	KCNQ1: PM2, PS3:Moderate, PS4:Moderate, PP4 -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.671C>T (p.T224M) alteration is located in exon 4 (coding exon 4) of the KCNQ1 gene. This alteration results from a C to T substitution at nucleotide position 671, causing the threonine (T) at amino acid position 224 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of <0.001% (1/248566) total alleles studied. The highest observed frequency was 0.001% (1/112482) of European (non-Finnish) alleles. This alteration has been detected in individuals with features of long QT syndrome; however clinical details were limited in some cases (Kapplinger, 2009; Roberts, 2017; Schwartz, 2009; Behr, 2013). This alteration has also been reported as an Amish founder mutation associated with a significant increase in QTc interval; however, it does appear to have low penetrance (Streeten, 2020). This alteration has also been reported in a homozygous state in a 6 year old female with prolonged QT and syncope (Mahdieh, 2020). This amino acid position is highly conserved in available vertebrate species. This alteration is located in the extracellular space between the S3 and S4 transmembrane helices. Functional studies suggest this variant may result in a reduction in current; however, these types of studies do not always reflect physiological significance (Streeten, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Cardiac arrhythmia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 26, 2023

This missense variant replaces threonine with methionine at codon 224 of the KCNQ1 protein. This variant is found within the highly conserved extracellular linker region (a.a. 218-225). Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study has shown that this variant causes a significant reduction in total activating and deactivating currents (PMID: 33141630). This variant has been reported in many individuals affected with long QT syndrome including two young homozygous individuals (PMID: 19716085, 19841298, 32470535, 33141630) and has been reported to segregate with disease in one family (PMID: 19841298). In particular, this variant has been reported to be a common cause of long QT syndrome in the Amish population with 34/88 (38.6%) of carriers versus 3/54 (5.5%) of non-carriers showing clinical evidence of long QT syndrome (P=0.0006) (PMID: 33141630). This study has suggested that the phenotypes associated with this variant appear to be mild. While this variant is observed at 1/45 frequency in the Amish population (PMID: 33141630), it is rare in the general population and has been identified in 1/248566 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

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:19716085). 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

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

.;D;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.77

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

.;L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.1

D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.95, 0.92

MutPred

0.85

.;Loss of sheet (P = 0.0063);.;

MVP

0.98

MPC

1.2

ClinPred

0.99

GERP RS

4.3

Varity_R

0.87

gMVP

0.91

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