21-34449472-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2
The NM_000219.6(KCNE1):c.163G>A(p.Gly55Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000615 in 1,202,928 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000219.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000482 AC: 5AN: 103632Hom.: 0 Cov.: 16
GnomAD3 exomes AF: 0.000127 AC: 32AN: 251428Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135910
GnomAD4 exome AF: 0.0000628 AC: 69AN: 1099208Hom.: 4 Cov.: 21 AF XY: 0.0000806 AC XY: 45AN XY: 557970
GnomAD4 genome AF: 0.0000482 AC: 5AN: 103720Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0AN XY: 50074
ClinVar
Submissions by phenotype
not provided Uncertain:2
Reported in one individual referred for LQTS genetic testing (Kapplinger et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported as a variant of uncertain significance by other clinical laboratories in ClinVar (SCV000549147.3, SCV000198416.4; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 24710009, 19716085, 31941373, 28988457) -
Variant KCNE1 p.Gly55Ser (c.163G>A) exon 4 (NM_000219.5, hg19 chr21-35821770-C-T) SCICD classification variant of uncertain significance, probably benign We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The rationale for this assessment is: too high MAF. (rs199473644, ExAC 0.07%)" 0.05198% MAF in South Asians -
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The Gly55Ser varian t in KCNE1 has not been previously reported in any individuals with hearing loss and was absent from large population studies. However, this variant has been re ported in one individual with long QT syndrome (Kapplinger 2009). The glycine (G ly) residue at position 55 is not conserved across several species including two mammals (hamster and mole) having serine (Ser) at this position, suggesting tha t the variant may be tolerated. However, this information is not sufficient to r ule out pathogenicity. In summary, the clinical significance of this variant can not be determined with certainty; however based upon the conservation data, we w ould lean towards a more likely benign role. -
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 glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 55 of the KCNE1 protein (p.Gly55Ser). This variant is present in population databases (rs199473644, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of LQTS (PMID: 19716085, 31941373). ClinVar contains an entry for this variant (Variation ID: 132657). 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 not expected to disrupt KCNE1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects KCNE1 function (PMID: 17545244). 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 Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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