rs199473354

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_000219.6(KCNE1):​c.154G>A​(p.Gly52Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000923 in 1,082,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G52A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 16)
Exomes 𝑓: 9.2e-7 ( 0 hom. )

Consequence

KCNE1
NM_000219.6 missense

Scores

10
7
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 4.93
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a transmembrane_region Helical (size 22) in uniprot entity KCNE1_HUMAN there are 14 pathogenic changes around while only 3 benign (82%) in NM_000219.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.927
PP5
Variant 21-34449481-C-T is Pathogenic according to our data. Variant chr21-34449481-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 132654.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-34449481-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNE1NM_000219.6 linkuse as main transcriptc.154G>A p.Gly52Arg missense_variant 4/4 ENST00000399286.3 NP_000210.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNE1ENST00000399286.3 linkuse as main transcriptc.154G>A p.Gly52Arg missense_variant 4/41 NM_000219.6 ENSP00000382226 P1

Frequencies

GnomAD3 genomes
Cov.:
16
GnomAD4 exome
AF:
9.23e-7
AC:
1
AN:
1082960
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
549692
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:
0.00000128
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
16

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 16, 2020This sequence change replaces glycine with arginine at codon 52 of the KCNE1 protein (p.Gly52Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect KCNE1 protein function (PMID: 14499862, 27076034, 19907016). This variant has been observed in individual(s) with long QT syndrome (PMID: 14499862). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 132654). This variant is not present in population databases (ExAC no frequency). -
Congenital long QT syndrome Other:1
not provided, no classification providedliterature onlyCardiovascular 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:14499862;PMID:19907016). 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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.95
D;D;D;D;D;D;D;D
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.84
.;.;T;.;.;.;.;.
M_CAP
Pathogenic
0.43
D
MetaRNN
Pathogenic
0.93
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.8
M;M;M;M;M;M;M;M
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.80
T
PROVEAN
Uncertain
-4.2
D;.;.;D;D;D;D;D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.011
D;.;.;D;D;D;D;D
Sift4G
Uncertain
0.0050
D;D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;D;D;D
Vest4
0.85
MutPred
0.65
Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);Gain of MoRF binding (P = 0.0613);
MVP
0.97
MPC
0.47
ClinPred
0.99
D
GERP RS
4.4
Varity_R
0.45
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.

Other links and lift over

dbSNP: rs199473354; hg19: chr21-35821779; COSMIC: COSV100492391; API