chr21-34449342-C-T

Position:

chr21-34449342-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM5

The NM_000219.6(KCNE1):c.293G>A(p.Arg98Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,584,134 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R98W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000043 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000035 ( 1 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 1.83

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 Uncertain_significance. Variant got 4 ACMG points.

PM1

In a helix (size 13) in uniprot entity KCNE1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000219.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-34449343-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132676.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic=2, Likely_pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6 linkuse as main transcript	c.293G>A	p.Arg98Gln	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3 linkuse as main transcript	c.293G>A	p.Arg98Gln	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes

AF:

0.0000425

AC:

AN:

141054

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:

0.000218

Gnomad SAS

AF:

0.000237

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000626

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251414

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000353

AC:

AN:

1443080

Hom.:

Cov.:

AF XY:

0.0000320

AC XY:

AN XY:

718900

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000356

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.0000425

AC:

AN:

141054

Hom.:

Cov.:

AF XY:

0.0000439

AC XY:

AN XY:

68320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000218

Gnomad4 SAS

AF:

0.000237

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000626

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	KCNE1: PM2, PS4:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2024	Reported in a patient with presumed LQTS and in a patient with sensorineural hearing loss who also harbored variants in other hearing loss-associated genes (PMID: 27863619, 31941373); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24561134, 27863619, 31941373) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 16, 2017

The p.Arg98Gln variant in KCNE1 has been previously reported by our laboratory i n two unrelated Caucasian individuals with hearing loss. This variant has been i dentified in 11/246202 of the total chromosomes by the Genome Aggregation Databa se across several populations (gnomAD, http://gnomad.broadinstitute.org; dbSNP r s150454912). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational predic tion tools and conservation analyses suggest that this variant may not impact th e protein, though this information is not predictive enough to rule out pathogen icity. In summary, the clinical significance of the p.Arg98Gln variant is uncert ain. ACMG/AMP Criteria applied: BP4. -

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 22, 2021

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Sep 08, 2017

- -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 98 of the KCNE1 protein (p.Arg98Gln). This variant is present in population databases (rs150454912, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with KCNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 228764). 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. This variant disrupts the p.Arg98 amino acid residue in KCNE1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16922724, 17341399, 19907016, 30530868). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Dec 12, 2022

The p.R98Q variant (also known as c.293G>A), located in coding exon 1 of the KCNE1 gene, results from a G to A substitution at nucleotide position 293. The arginine at codon 98 is replaced by glutamine, an amino acid with highly similar properties. This variant was detected in a control group with baseline QTc interval less than 470ms in a study of drug-induced long QT syndrome (LQTS) (Weeke P et al. J. Am. Coll. Cardiol. 2014;63:1430-7), and was also detected in a proband with hearing loss and no mention of cardiac arrhythmia, who also had variants in other hearing loss-associated genes (Li Y et al. Int. J. Pediatr. Otorhinolaryngol. 2016;91:1-5). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

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

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.86

.;.;D;.;.;.;.;.

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.43

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

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.7

M;M;M;M;M;M;M;M

MutationTaster

Benign

0.62

N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.87

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

REVEL

Uncertain

0.64

Sift

Uncertain

0.0080

D;.;.;D;D;D;D;D

Sift4G

Uncertain

0.033

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

Polyphen

0.99

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

Vest4

0.25

MVP

0.89

MPC

0.45

ClinPred

0.17

GERP RS

4.9

Varity_R

0.13

gMVP

0.63

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