rs199472768
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000218.3(KCNQ1):c.1135T>C(p.Trp379Arg) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W379S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000218.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.1135T>C | p.Trp379Arg | missense_variant | 9/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1135T>C | p.Trp379Arg | missense_variant | 9/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.754T>C | p.Trp252Arg | missense_variant | 9/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.778T>C | p.Trp260Arg | missense_variant | 9/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.595T>C | p.Trp199Arg | missense_variant | 4/11 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Long QT syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 26066609). 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. ClinVar contains an entry for this variant (Variation ID: 67013). This missense change has been observed in individuals with long QT syndrome (PMID: 16534005, 26066609; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 379 of the KCNQ1 protein (p.Trp379Arg). - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | May 31, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2020 | Reported in association with LQTS (Vyas et al., 2006; Tester et al., 2007; Steffensen et al., 2015); Reported in ClinVar (ClinVar Variant ID# 67013; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; While in vitro functional studies suggest that this variant may impact channel function (Steffensen et al., 2015), it is unclear how these studies may translate to a pathogenic role in vivo; This variant is associated with the following publications: (PMID: 22581653, 31535183, 22677073, 17222736, 16534005, 26066609, 31892348) - |
SUDDEN INFANT DEATH 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 Sudden infant death syndrome in the following publications (PMID:17222736;PMID:22677073). 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