rs120074182

Positions:

• chr11-2583448-C-T

Variant summary

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

The NM_000218.3(KCNQ1):​c.935C>T​(p.Thr312Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. T312S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.42

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 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2583447-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522585.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-2583448-C-T is Pathogenic according to our data. Variant chr11-2583448-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2583448-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.935C>T	p.Thr312Ile	missense_variant	7/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.935C>T	p.Thr312Ile	missense_variant	7/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.554C>T	p.Thr185Ile	missense_variant	7/16	1
KCNQ1	ENST00000496887.7	c.674C>T	p.Thr225Ile	missense_variant	8/16	5
KCNQ1	ENST00000646564.2	c.491C>T	p.Thr164Ile	missense_variant	3/11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1996

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2020

Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate a damaging effect as the T312I variant results in an inactive potassium channel (Shalaby et al., 1997; Westenskow et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15051636, 22456477, 14678125, 27114410, 15466642, 22949429, 9323054, 23153844, 19815527, 19841300, 19862833, 26669661, 17470695, 19716085, 10973849, 15840476, 25734225, 8528244, 20368164) -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 18, 2023

ClinVar contains an entry for this variant (Variation ID: 3116). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 312 of the KCNQ1 protein (p.Thr312Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 8528244, 10973849, 15051636, 21451124, 22727609, 25294783; Invitae). This variant is also known as p.Thr183Ile and p.Thr311Ile. 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. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 9323054, 15051636, 15498462, 20368164, 22456477). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2020

The p.T312I variant (also known as c.935C>T), located in coding exon 7 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 935. The threonine at codon 312 is replaced by isoleucine, an amino acid with similar properties. This alteration has been detected in several long QT syndrome (LQTS) cohorts (Wang Q et al. Nat. Genet., 1996 Jan;12:17-23; Splawski I et al. Circulation, 2000 Sep;102:1178-85; Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Vijayakumar R et al. Circulation, 2014 Nov;130:1936-1943), as well as in two children who experienced sudden unexplained death (SUD) and near drowning events (Anderson JH et al. Circ Cardiovasc Genet, 2016 Jun;9:259-65; Choi G et al. Circulation, 2004 Oct;110:2119-24). In addition, several functional studies demonstrated >50% current reduction in T312I channels compared to wild type (Jons C et al. Sci Transl Med, 2011 Mar;3:76ra28; Barsheshet A et al. Circulation, 2012 Apr;125:1988-96; Shalaby FY et al. Circulation, 1997 Sep;96:1733-6; Hoefen R et al. J. Am. Coll. Cardiol., 2012 Nov;60:2182-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 15, 2021

This missense variant replaces threonine with isoleucine at codon 312 in the conserved pore-forming region of the KCNQ1 protein. Computational prediction 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. Functional studies have been shown that this variant has a dominant negative effect on the potassium channel function in vitro (PMID: 9323054, 22456477) and results in a phenotype similar to Jervell and Lange-Nielsen syndrome, an autosomal recessive form of familial long QT syndrome, in mice (PMID 15498462, 20368164; this variant is referred to as T311I in these articles). This variant has been reported in many individuals affected with long QT syndrome (PMID: 10973849, 14678125, 15051636, 15466642, 15840476, 17470695, 19841300, 22456477, 22727609, 25294783). 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:8528244;PMID:9323054;PMID:10973849;PMID:14678125;PMID:15051636;PMID:15466642;PMID:15840476;PMID:19716085;PMID:19841300;PMID:20368164;PMID:17470695;PMID:22456477). 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	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.5	D;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0010	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.91		Loss of catalytic residue at T312 (P = 0.0378);.;.;
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.95
gMVP		1.0

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: rs120074182; hg19: chr11-2604678;