NM_000219.6:c.247G>A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000219.6(KCNE1):c.247G>A(p.Glu83Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000425 in 1,460,276 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000219.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000416 AC: 6AN: 144174Hom.: 0 Cov.: 17
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251428Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135910
GnomAD4 exome AF: 0.0000425 AC: 62AN: 1460276Hom.: 1 Cov.: 30 AF XY: 0.0000372 AC XY: 27AN XY: 726520
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000416 AC: 6AN: 144284Hom.: 0 Cov.: 17 AF XY: 0.0000714 AC XY: 5AN XY: 70028
ClinVar
Submissions by phenotype
not provided Uncertain:2
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24710009, 19716085, 26159999, 26410412, 34426522) -
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not specified Uncertain:1
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in small number of probands; ExAC: 1/11570 Latino; ClinVar: 1 P (lit only) -
Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 Uncertain:1
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Long QT syndrome Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 83 of the KCNE1 protein (p.Glu83Lys). This variant is present in population databases (rs199473360, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of KCNE1-related conditions (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 132673). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNE1 protein function. 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 p.E83K variant (also known as c.247G>A) is located in coding exon 1 of the KCNE1 gene. This alteration results from a G to A substitution at nucleotide position 247. The glutamic acid at codon 83 is replaced by lysine, an amino acid with similar properties. In a study of long QT syndrome clinical genetic testing, this alteration was reported in one patient; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). This alteration was also reported in an individual from a healthy exome cohort with a normal QTc interval, but additional clinical information was not available (Ghouse J et al. Eur. Heart J., 2015 Oct;36:2523-9). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, 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:19716085). 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