rs17857111

chr21-34449540-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5 BP4_Moderate

The NM_000219.6(KCNE1):c.95G>A(p.Arg32His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign 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. R32C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 0.000056 (18 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 O:1
• Conservation: PhyloP100: 1.12

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-34449541-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.14678806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6	c.95G>A	p.Arg32His	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3	c.95G>A	p.Arg32His	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251328 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000561 AC: 48 AN: 854856 Hom.: 18 Cov.: 22 AF XY: 0.0000588 AC XY: 25 AN XY: 425282

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000141

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000445

Gnomad4 OTH exome AF: 0.0000572

GnomAD4 genome Cov.: 12

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000494 AC: 6

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 05, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2021	Also identified in patients with atrioventricular nodal reentrant tachycardia and ventricular fibrillation (Hasdemir et al., 2015; Leinonen et al., 2018); Published functional studies demonstrate R32H results in a 22% decrease in the amplitude of potassium channel current compared to wild-type; however, the clinical relevance of this finding is uncertain (Westenskow et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11692163, 24710009, 24478792, 15051636, 23098067, 26675252, 19862833, 17341399, 19716085, 25998140, 18752142, 10973849, 29032884, 30461122, 23174487, 22581653, 19214780, 33373586) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 05, 2018

Variant summary: KCNE1 c.95G>A (p.Arg32His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 246544 control chromosomes. The observed variant frequency is approximately 5-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in KCNE1 causing Arrhythmia phenotype (1e-05), suggesting that the variant might be benign. c.95G>A has been reported in the literature in individuals affected with Long QT Syndrome (LQTS) or referred for Arrhythmia genetic testing (Berge_2008, Hasemir_2015, Kapplinger_2009, Schulze-Bahr_2001, Splawski_2000), including one homozygous individual with a mild QTc prolongation (447 ms) (Stattin_2012). In one family the variant was found in co-occurrence with another pathogenic variant (SCN5A c.4931G>A (p.Arg1644His)), resulting in a variable penetrance ranging from severe to mild phenotypes (Westenskow_2004). These reports do not provide unequivocal conclusions about an association of the variant with Arrhythmia. A functional study found that when the variant protein was co-expressed with the WT (to mimic heterozygosity), it did not affect gating, however it decreased the amplitude of the potassium channel current (IKs) to 78% of the WT (Westenskow_2004). Two ClinVar Submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 12, 2021

- -

Jervell and Lange-Nielsen syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 32 of the KCNE1 protein (p.Arg32His). This variant is present in population databases (rs17857111, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of KCNE1-related conditions (PMID: 10973849, 15051636, 18752142, 19716085, 23098067, 25998140, 26675252, 29032884). ClinVar contains an entry for this variant (Variation ID: 132683). 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. Experimental studies have shown that this missense change does not substantially affect KCNE1 function (PMID: 15051636). 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

Nov 04, 2021

The c.95G>A (p.R32H) alteration is located in exon 3 (coding exon 1) of the KCNE1 gene. This alteration results from a G to A substitution at nucleotide position 95, causing the arginine (R) at amino acid position 32 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital long QT 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 Long QT syndrome in the following publications (PMID:10973849;PMID:15051636;PMID:18752142;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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	20
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D;D;D;D;D;D;D;D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.60	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.6	M;M;M;M;M;M;M;M
MutationTaster	Benign	0.94	N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.47	N;.;.;N;N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.073	T;.;.;T;T;T;T;T
Sift4G	Benign	0.53	T;T;T;T;T;T;T;T
Polyphen		0.010	B;B;B;B;B;B;B;B
Vest4		0.064
MutPred		0.36		Loss of methylation at R32 (P = 0.0393);Loss of methylation at R32 (P = 0.0393);Loss of methylation at R32 (P = 0.0393);Loss of methylation at R32 (P = 0.0393);Loss of methylation at R32 (P = 0.0393);Loss of methylation at R32 (P = 0.0393);Loss of methylation at R32 (P = 0.0393);Loss of methylation at R32 (P = 0.0393);
MVP		0.93
MPC		0.10
ClinPred		0.10	T
GERP RS		2.9
Varity_R		0.038
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17857111; hg19: chr21-35821838; COSMIC: COSV61606738;