rs199473646

chr21-34449426-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000219.6(KCNE1):c.209A>T(p.Lys70Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,788 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K70N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 4.08

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 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000219.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-34449425-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNE1	NM_000219.6	c.209A>T	p.Lys70Met	missense_variant	4/4	ENST00000399286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNE1	ENST00000399286.3	c.209A>T	p.Lys70Met	missense_variant	4/4	1	NM_000219.6	P1

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251404 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442788 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 718822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 17

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 12, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.Lys70 amino acid residue in KCNE1. Other variant(s) that disrupt this residue have been observed in individuals with KCNE1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects KCNE1 function (PMID: 21576493). ClinVar contains an entry for this variant (Variation ID: 132663). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 31941373; Invitae). This variant is present in population databases (rs199473646, gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 70 of the KCNE1 protein (p.Lys70Met). -

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:19716085). 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	0.92
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;D;D;D;D;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	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	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.4	D;.;.;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;.;.;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D
Vest4		0.44
MutPred		0.43		Loss of ubiquitination at K70 (P = 0.0141);Loss of ubiquitination at K70 (P = 0.0141);Loss of ubiquitination at K70 (P = 0.0141);Loss of ubiquitination at K70 (P = 0.0141);Loss of ubiquitination at K70 (P = 0.0141);Loss of ubiquitination at K70 (P = 0.0141);Loss of ubiquitination at K70 (P = 0.0141);Loss of ubiquitination at K70 (P = 0.0141);
MVP		0.97
MPC		0.49
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.39
gMVP		0.80

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: rs199473646; hg19: chr21-35821724;