rs199473351

Positions:

chr21-34449528-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000219.6(KCNE1):c.107G>A(p.Arg36His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000025 ( 1 hom., cov: 12)

Exomes 𝑓: 0.000034 ( 13 hom. )

Failed GnomAD Quality Control

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1O:2

Conservation

PhyloP100: -0.144

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08337629).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE1	NM_000219.6 linkuse as main transcript	c.107G>A	p.Arg36His	missense_variant	4/4	ENST00000399286.3	NP_000210.2	P15382C7S316Q6FHJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3 linkuse as main transcript	c.107G>A	p.Arg36His	missense_variant	4/4	1	NM_000219.6	ENSP00000382226.2		P15382

Frequencies

GnomAD3 genomes

AF:

0.0000248

AC:

AN:

80688

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000522

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

251362

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000343

AC:

AN:

846664

Hom.:

Cov.:

AF XY:

0.0000428

AC XY:

AN XY:

420998

show subpopulations

Gnomad4 AFR exome

AF:

0.000122

Gnomad4 AMR exome

AF:

0.0000698

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000613

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000340

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000248

AC:

AN:

80688

Hom.:

Cov.:

AF XY:

0.0000507

AC XY:

AN XY:

39430

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000522

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000155

Hom.:

ExAC

AF:

0.0000906

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 31, 2019	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg36His variant in KCNE1 has been previously identified in 1 Caucasian individual with long QT syndrome (Napolitano 2005) and 1 individual with hearing loss by our laboratory. It has also been identified in 11/121094 of the total chromosomes across several populations by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199473351). Computational prediction tools and conservation analysis suggest that the p.Arg36His variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Arg36His variant is uncertain. ACMG/AMP criteria applied: PM2_Supporting, BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 28, 2024	Variant summary: KCNE1 c.107G>A (p.Arg36His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251362 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 65 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNE1 causing Long QT Syndrome phenotype (2.1e-06). c.107G>A has been reported in the literature in individuals affected with Long QT Syndrome (Napolitano_2005, Lane_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, suggesting that the variant results in a mild reduction in IKv7.1 current density in vitro (Lane_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29625280, 16414944, 32451364). ClinVar contains an entry for this variant (Variation ID: 132650). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2025	Published functional studies in cultured cells showed that, in the heterozygous state, p.(R36H) reduces the slow delayed rectifier potassium current density (Iks), supporting that this variant may have a loss of function effect (PMID: 29625280); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30461122, 24710009, 28988457, 29625280, 17341399, 27965898, 34426522, 34667425, 16414944) -

Long QT syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Oct 01, 2016	Found in patient having exome sequencing for an unrelated indication. No known history of long QT syndrome. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2022

The c.107G>A (p.R36H) 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 107, causing the arginine (R) at amino acid position 36 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Long QT syndrome 5

Other:1

not provided, no classification provided

in vitro

Roden Lab, Vanderbilt University Medical Center

- -

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:16414944). 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

0.070

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Uncertain

0.59

D;D;D;D;D;D;D;D

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.53

.;.;T;.;.;.;.;.

M_CAP

Benign

0.074

MetaRNN

Benign

0.083

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.90

L;L;L;L;L;L;L;L

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.60

N;.;.;N;N;N;N;N

REVEL

Uncertain

0.50

Sift

Benign

0.12

T;.;.;T;T;T;T;T

Sift4G

Benign

0.20

T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;B;B;B;B

Vest4

0.23

MVP

0.64

MPC

0.13

ClinPred

0.019

GERP RS

1.0

Varity_R

0.026

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over