rs200963514

Positions:

chr21-34449541-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5BP4BS2

The NM_000219.6(KCNE1):c.94C>T(p.Arg32Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 939,432 control chromosomes in the GnomAD database, including 4 homozygotes. 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. R32H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000012 ( 0 hom., cov: 12)

Exomes 𝑓: 0.000015 ( 4 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.33

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 -3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-34449540-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.2682593).

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6 linkuse as main transcript	c.94C>T	p.Arg32Cys	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.94C>T	p.Arg32Cys	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes

AF:

0.0000124

AC:

AN:

80624

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:

0.0000261

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251346

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

858766

Hom.:

Cov.:

AF XY:

0.0000211

AC XY:

AN XY:

427508

show subpopulations

Gnomad4 AFR exome

AF:

0.000118

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000168

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000124

AC:

AN:

80666

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

39360

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:

0.0000261

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2018	The R32C variant has been observed in three of four relatives from a family with LQTS (McGorrian et al., 2013). Specific clinical details for the these family members were not provided, therefore, it was unclear which, if any, of these relatives carried a diagnosis of LQTS. Furthermore, one individual also harbored a reportedly de novo variant in the KCNH2 gene. This family includes one relative with a diagnosis of sudden arrhythmic death, though it was not clear whether this individual also had a diagnosis of LQTS or was included in those relatives from this family who received molecular analysis. The R32C variant has also been reported in one individual from a cohort of individuals not selected for a history of cardiomyopathy, arrhythmia or family history of sudden cardiac death who underwent exome sequencing (Ng et al., 2013); however, no follow-up cardiac evaluation was reported. The R32C variant is observed in 3/33580 (0.0089%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The R32C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret the R32C variant as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Nov 09, 2021	- -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 32 of the KCNE1 protein (p.Arg32Cys). This variant is present in population databases (rs200963514, gnomAD 0.009%). This missense change has been observed in individual(s) with sudden unexpected death (PMID: 23382499). ClinVar contains an entry for this variant (Variation ID: 191466). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on KCNE1 function (PMID: 24314077). 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

Jun 06, 2022

The p.R32C variant (also known as c.94C>T), located in coding exon 1 of the KCNE1 gene, results from a C to T substitution at nucleotide position 94. The arginine at codon 32 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in family members of a sudden death case; however, clinical details were limited and a co-occurring KCNH2 variant was also reported in one individual (McGorrian C et al. Europace, 2013 Jul;15:1050-8). This alteration has also been reported as a secondary cardiac variant in an exome cohort; however, clinical details are limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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

0.15

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

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

Eigen

Benign

0.0078

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.77

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

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.27

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

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.6

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

MutationTaster

Benign

0.98

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

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.5

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

REVEL

Pathogenic

0.78

Sift

Uncertain

0.015

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

Sift4G

Benign

0.15

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

Polyphen

0.023

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

Vest4

0.29

MutPred

0.50

Loss of disorder (P = 0.0242);Loss of disorder (P = 0.0242);Loss of disorder (P = 0.0242);Loss of disorder (P = 0.0242);Loss of disorder (P = 0.0242);Loss of disorder (P = 0.0242);Loss of disorder (P = 0.0242);Loss of disorder (P = 0.0242);

MVP

0.95

MPC

0.46

ClinPred

0.62

GERP RS

3.9

Varity_R

0.12

gMVP

0.57

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