rs17857111

Variant names:

• chr21-34449540-C-T
• rs17857111
• NM_000219.6:c.95G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 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. R32L) 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
• Publications: 11 publications found

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]

KCNE1 Gene-Disease associations (from GenCC):

• long QT syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Jervell and Lange-Nielsen syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a mutagenesis_site Increase in inhibition of the complex KCNQ1-KCNE1 by the scolopendra toxin SSD609. (size 0) in uniprot entity KCNE1_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.14678806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.95G>A	p.Arg32His	missense_variant	Exon 4 of 4	ENST00000399286.3	NP_000210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3	c.95G>A	p.Arg32His	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251328 AF XY: 0.0000442

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 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

African (AFR) AF: 0.00 AC: 0 AN: 16832

American (AMR) AF: 0.00 AC: 0 AN: 29172

Ashkenazi Jewish (ASJ) AF: 0.000141 AC: 2 AN: 14208

East Asian (EAS) AF: 0.00 AC: 0 AN: 19692

South Asian (SAS) AF: 0.000243 AC: 12 AN: 49412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35904

Middle Eastern (MID) AF: 0.000862 AC: 3 AN: 3482

European-Non Finnish (NFE) AF: 0.0000445 AC: 29 AN: 651182

Other (OTH) AF: 0.0000572 AC: 2 AN: 34972

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

Aug 05, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 05, 2018

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jervell and Lange-Nielsen syndrome 2 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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 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

Nov 04, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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
LIST_S2	Benign	0.65	.;.;T;.;.;.;.;.
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
PhyloP100		1.1
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		0.036
gMVP		0.52
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

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