rs199473354

Positions:

• chr21-34449481-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:2
• Conservation: PhyloP100: 4.93

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]

ACMG classification

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
KCNE1	NM_000219.6	c.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
KCNE1	ENST00000399286.3	c.154G>A	p.Gly52Arg	missense_variant	4/4	1	NM_000219.6	ENSP00000382226.2

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

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:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2020

This 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). -

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: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
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

Other links and lift over

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