rs120074182
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_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
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at