21-34449393-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000219.6(KCNE1):c.242A>G(p.Tyr81Cys) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y81F) has been classified as Benign.
Frequency
Consequence
NM_000219.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 18
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251436Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135914
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 18
ClinVar
Submissions by phenotype
not provided Uncertain:1
Published functional studies suggest a dominant negative effect (Wu et al., 2006); Reported in ClinVar as a variant of uncertain significance but additional evidence is not available (ClinVar Variant ID# 132671; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16945797, 22581653, 16945798, 24710009, 17341399, 16155735, 30530868) -
Long QT syndrome Uncertain:1
This sequence change replaces tyrosine with cysteine at codon 81 of the KCNE1 protein (p.Tyr81Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 16155735). ClinVar contains an entry for this variant (Variation ID: 132671). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNE1 function (PMID: 16945797). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiovascular phenotype Uncertain:1
The c.242A>G (p.Y81C) alteration is located in exon 3 (coding exon 1) of the KCNE1 gene. This alteration results from a A to G substitution at nucleotide position 242, causing the tyrosine (Y) at amino acid position 81 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Long QT syndrome 5 Other:1
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Congenital long QT syndrome Other:1
This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16155735;PMID:16945797). 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