rs747321794
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM5PP5
The NM_000219.6(KCNE1):c.173C>T(p.Thr58Ile) variant causes a missense change. 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. T58A) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 17)
Exomes 𝑓: 0.0000053 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KCNE1
NM_000219.6 missense
NM_000219.6 missense
Scores
3
11
5
Clinical Significance
Conservation
PhyloP100: 6.68
Genes affected
KCNE1 (HGNC:6240): (potassium voltage-gated channel subfamily E regulatory subunit 1) The product of this gene belongs to the potassium channel KCNE family. Potassium ion channels are essential to many cellular functions and show a high degree of diversity, varying in their electrophysiologic and pharmacologic properties. This gene encodes a transmembrane protein known to associate with the product of the KVLQT1 gene to form the delayed rectifier potassium channel. Mutation in this gene are associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long-QT syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000219.6
PM5
Other missense variant is known to change same aminoacid residue: Variant chr21-34449463-T-G is described in Lovd as [Pathogenic].
PP5
Variant 21-34449462-G-A is Pathogenic according to our data. Variant chr21-34449462-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372392.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNE1 | NM_000219.6 | c.173C>T | p.Thr58Ile | missense_variant | 4/4 | ENST00000399286.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNE1 | ENST00000399286.3 | c.173C>T | p.Thr58Ile | missense_variant | 4/4 | 1 | NM_000219.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 115418Hom.: 0 Cov.: 17 FAILED QC
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251410Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135906
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000526 AC: 6AN: 1141764Hom.: 0 Cov.: 20 AF XY: 0.00000346 AC XY: 2AN XY: 578700
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GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 115418Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0AN XY: 55534
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 16, 2016 | The T58I variant that is likely pathogenic was identified in the KCNE1 gene. It has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.However, this variant has been reported in one other individual referred for LQTS genetic testing atGeneDx. The T58I variant was not observed in approximately 6,500 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a commonbenign variant in these populations. The T58I variant is a non-conservative amino acid substitution,which is likely to impact secondary protein structure as these residues differ in polarity, charge, sizeand/or other properties, and this substitution occurs at a position that is conserved across species. Alikely pathogenic variant at the same residue (T58P) has been reported in the Human Gene MutationDatabase in association with LQTS (Stenson et al., 2014), supporting the functional importance ofthis residue. Furthermore, functional studies of the KCNE1 gene by Melman et al. (2002) concludedthat T58, the central amino acid of a triplet responsible for the specificity of KCNE1 control ofactivation of the potassium channel, is essential for the specific control of voltage-dependent channelactivation characteristics. However, in silico analysis is inconsistent in its predictions as to whether ornot the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic. - |
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Aug 29, 2017 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 02, 2019 | The KCNE1 c.173C>T; p.Thr58Ile variant (rs747321794) is reported in the literature in at least one individual affected with long QT syndrome (Faridi 2019). Additionally, another variant at this codon (c.172A>C; p.Thr58Pro) has been reported in individuals with long QT syndrome (Kapplinger 2009). The p.Thr58Ile variant is reported in ClinVar (Variation ID: 372392), and is found in the Latino population with an allele frequency of 0.023% (8/35,440 alleles) in the Genome Aggregation Database. The threonine at codon 58 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: probably damaging) predict conflicting effects of this variant on protein structure/function. However, functional analyses of the KCNE1 protein show that threonine 58 is critical for specific control of the voltage-dependent potassium channel, and that the p.Thr58Ile variant results in voltage-independent activation in vitro (Melman 2002). Due to limited information, the clinical significance of the p.Thr58Ile variant is uncertain at this time. References: Faridi R et al. Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome. Hum Mutat. 2019 Feb;40(2):162-176. Kapplinger JD et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. Melman YF et al. A single transmembrane site in the KCNE-encoded proteins controls the specificity of KvLQT1 channel gating. J Biol Chem. 2002 Jul 12;277(28):25187-94. - |
SUDDEN INFANT DEATH SYNDROME Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Robert's Program, Boston Children's Hospital | Oct 01, 2021 | We classify this variant as a variant of uncertain significance using ACMG/AMP criteria. As this variant has functional evidence supporting pathogenicty, we suspect this variant is favoring pathogenic. - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 18, 2023 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 58 of the KCNE1 protein (p.Thr58Ile). This variant is present in population databases (rs747321794, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 30461122). ClinVar contains an entry for this variant (Variation ID: 372392). 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 08, 2023 | The p.T58I variant (also known as c.173C>T), located in coding exon 1 of the KCNE1 gene, results from a C to T substitution at nucleotide position 173. The threonine at codon 58 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in a long QT syndrome cohort and a sudden unexplained death cohort; however, clinical details were limited in both cases (Faridi R et al. Hum Mutat, 2019 Feb;40:162-176; Koh HY et al. Genet Med, 2022 Apr;24:839-850). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;D;D;D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;.;T;.;.;.;.;.
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;M;M;M;M
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;.;.;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T
Polyphen
D;D;D;D;D;D;D;D
Vest4
MutPred
Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP
MPC
0.45
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at