11-2583448-C-T

Variant names:

• chr11-2583448-C-T
• rs120074182
• NM_000218.3:c.935C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 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. 13/23 in silico tools predict a damaging 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:7 O:1
• Conservation: PhyloP100: 7.42
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 33 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 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 VariationId is 522585.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 3116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.935C>T	p.Thr312Ile	missense_variant	Exon 7 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.935C>T	p.Thr312Ile	missense_variant	Exon 7 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:2

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene (OMIM, PMID: 19632626). (N) 0104 - Dominant negative is a mechanism of disease for this gene (OMIM, PMID: 19632626). (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance (GeneReviews). (N) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif. The variant is located in the pore domain (PDB). (N) 0704 - Comparable variant has low previous evidence for pathogenicity [p.(Thr312Ser) has one likely pathogenic entry in ClinVar for a LQTS patient]. (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. Two pathogenic entries in ClinVar and has been identified in >15 LQTS patients (PMID: 19716085, PMID: 17470695) (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) – Pathogenic, (N) – Neutral, (B) – Benign -

Jan 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Mar 31, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

May 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KCNQ1 c.935C>T; p.Thr312Ile variant (rs120074182, ClinVar Variation ID: 3116), also known as T183I or T311I, is reported in the literature in several individuals affected with long QT syndrome, arrhythmia, or sudden unexplained death (Anderson 2016, Giudicessi 2012, Sarquella-Brugada 2022, Wang 1996, Westenskow 2004). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.982). Functional analyses of the variant protein show disrupted protein channel activity (Shalaby 1997, Sarquella-Brugada 2004). Based on available information, this variant is considered to be pathogenic. References: Anderson JH et al. Whole-Exome Molecular Autopsy After Exertion-Related Sudden Unexplained Death in the Young. Circ Cardiovasc Genet. 2016 Jun;9(3):259-65. PMID: 27114410. Giudicessi JR et al. Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. PMID: 22949429. Sarquella-Brugada G et al. Clinical impact of rare variants associated with inherited channelopathies: a 5-year update. Hum Genet. 2022 Oct;141(10):1579-1589. PMID: 34546463. Shalaby FY et al. Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome. Circulation. 1997 Sep 16;96(6):1733-6. PMID: 9323054. Wang Q et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996 Jan;12(1):17-23. PMID: 8528244. Westenskow P et al. Compound mutations: a common cause of severe long-QT syndrome. Circulation. 2004 Apr 20;109(15):1834-41. PMID: 15051636. -

Long QT syndrome Pathogenic:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). This variant is also known as p.Thr183Ile and p.Thr311Ile. ClinVar contains an entry for this variant (Variation ID: 3116). 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, 15051636, 15498462, 20368164, 22456477). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

May 14, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T312I pathogenic mutatoin (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 variant was reported in individual(s) with features consistent with long QT syndrome (Westenskow P et al. Circulation. 2004 Apr;109(15):1834-41; Andrsova I et al. J Electrocardiol. Jun;45(6):746-51; Barsheshet A et al. Circulation. 2012 Apr;125(16):1988-96; Giudicessi JR et al. Circ Cardiovasc Genet. 2012 Oct;5(5):519-28; Vijayakumar R et al. Circulation, 2014 Nov;130:1936-1943; Samol A et al. PLoS One. 2016 Jul;11(7):e0158085; Sarquella-Brugada G et al. Hum Genet. 2022 Oct;141(10):1579-1589; Ambry internal data). In multiple assays testing KCNQ1 function, this variant showed functionally abnormal results (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. 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. -

Cardiac arrhythmia Pathogenic:1

Jun 15, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

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: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
CardioboostArm	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;.;.
PhyloP100		7.4
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs120074182; hg19: chr11-2604678;