21-34449435-C-A

Position:

chr21-34449435-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP3_Strong

The NM_000219.6(KCNE1):c.200G>T(p.Arg67Leu) variant causes a missense change. In-silico tool predicts a pathogenic 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. R67C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 17)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:1

Conservation

PhyloP100: 5.01

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_pathogenic. Variant got 8 ACMG points.

PM1

In a helix (size 25) in uniprot entity KCNE1_HUMAN there are 16 pathogenic changes around while only 5 benign (76%) in NM_000219.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-34449436-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE1	NM_000219.6 linkuse as main transcript	c.200G>T	p.Arg67Leu	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.200G>T	p.Arg67Leu	missense_variant	4/4	1	NM_000219.6	ENSP00000382226.2		P15382

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251394

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000285

AC:

AN:

1404598

Hom.:

Cov.:

AF XY:

0.00000428

AC XY:

AN XY:

701304

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000283

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26179811, 28600387, 30461122, 31941373, 26582918, 27535533) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 10, 2023	The KCNE1 c.200G>T; p.Arg67Leu variant (rs79654911) is reported in the literature in individuals with idiopathic cardiac arrest or long QT syndrome (Mellor 2017, Roberts 2020). This variant is also reported in ClinVar (Variation ID: 418269). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.91). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 11, 2023

This missense change has been observed in individual(s) with Long QT syndrome (PMID: 31941373). 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. This variant disrupts the p.Arg67 amino acid residue in KCNE1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31941373). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 418269). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 67 of the KCNE1 protein (p.Arg67Leu). -

Long QT syndrome 5

Other:1

not provided, no classification provided

in vitro

Roden Lab, Vanderbilt University Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

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

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.80

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

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.94

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

MetaSVM

Pathogenic

0.94

MutationAssessor

Uncertain

2.4

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

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.4

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

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0040

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

Polyphen

0.55

P;P;P;P;P;P;P;P

Vest4

0.93

MutPred

0.79

Loss of disorder (P = 0.0565);Loss of disorder (P = 0.0565);Loss of disorder (P = 0.0565);Loss of disorder (P = 0.0565);Loss of disorder (P = 0.0565);Loss of disorder (P = 0.0565);Loss of disorder (P = 0.0565);Loss of disorder (P = 0.0565);

MVP

0.96

MPC

0.38

ClinPred

0.99

GERP RS

5.2

Varity_R

0.72

gMVP

0.88

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