rs199472805

Positions:

• chr11-2777000-T-C
• chr11-2777000-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000155840.12(KCNQ1):​c.1700T>C​(p.Ile567Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,834 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I567S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNQ1 ENST00000155840.12 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 4.52

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in ENST00000155840.12
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2776999-A-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 11-2777000-T-C is Pathogenic according to our data. Variant chr11-2777000-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2777000-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1700T>C	p.Ile567Thr	missense_variant	14/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1700T>C	p.Ile567Thr	missense_variant	14/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.1319T>C	p.Ile440Thr	missense_variant	14/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.1343T>C	p.Ile448Thr	missense_variant	14/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.1160T>C	p.Ile387Thr	missense_variant	9/11			ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727214

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 567 of the KCNQ1 protein (p.Ile567Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (LQTs) and/or Jervell and Lange-Nielsen syndrome (JLNS) (PMID: 16414944, 19716085, 22429796, 23130128, 24372464). ClinVar contains an entry for this variant (Variation ID: 53007). 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) has been performed at Invitae 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. This variant disrupts the p.Ile567 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17470695, 22456477). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

Long QT syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Sep 15, 2020

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2022

Reported in association with Long QT syndrome (Napolitano et al., 2005; Kapplinger et al., 2009; Obeyesekere et al., 2012; Crotti et al., 2012; Couderc et al., 2012; Izumi et al., 2016; Wong et al., 2019); 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: 27041096, 23130128, 25981146, 24372464, 22429796, 16414944, 28438721, 23158531, 31424047, 19716085) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2023

The p.I567T pathogenic mutation (also known as c.1700T>C), located in coding exon 14 of the KCNQ1 gene, results from a T to C substitution at nucleotide position 1700. The isoleucine at codon 567 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in association with long QT syndrome (LQTS) (Napolitano C, JAMA 2005 Dec; 294(23):2975-80; Kapplinger JD, Heart Rhythm 2009 Sep; 6(9):1297-303; Obeyesekere MN, J. Cardiovasc. Electrophysiol. 2012 Jun; 23(6):637-42; Wong AR et al. Med J Malaysia, 2019 Aug;74:341-343; Yee LA et al. J Am Heart Assoc, 2022 Sep;11:e025108). This alteration has also been reported as homozygous in subjects with deafness and prolonged QT (Al-Aama JY et al. Clin. Genet., 2015 Dec;87:74-9; Al-Hassnan ZN et al. Heart Rhythm, 2017 Aug;14:1191-1199). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 20, 2019

This missense variant replaces isoleucine with threonine at codon 567 in the cytoplasmic C-terminal region of the KCNQ1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ≥0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with long QT syndrome (PMID: 16414944, 22429796, 23130128, 29925740, 31424047) and in an individual referred for long QT syndrome genetic testing (PMID: 19716085). This variant has been reported in the homozygous state in individuals affected with Jervell and Lange-Nielsen syndrome (PMID: 24372464). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely 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:16414944;PMID:19716085;PMID:22429796). 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	0.65
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.0	D;.;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.021	D;.;D
Sift4G	Uncertain	0.0080	D;.;D
Polyphen		0.71	P;.;P
Vest4		0.77
MutPred		0.92		Loss of stability (P = 0.0361);.;.;
MVP		0.98
MPC		1.1
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.54
gMVP		0.96

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

Other links and lift over

dbSNP: rs199472805; hg19: chr11-2798230;