NM_000219.6:c.200G>T

Variant names:

• chr21-34449435-C-A
• rs79654911
• NM_000219.6:c.200G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM5 PP3_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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 5.01

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 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 rank	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.200G>T	p.Arg67Leu	missense_variant	Exon 4 of 4	ENST00000399286.3	NP_000210.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3	c.200G>T	p.Arg67Leu	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251394 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135902

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: 4 AN: 1404598 Hom.: 0 Cov.: 26 AF XY: 0.00000428 AC XY: 3 AN XY: 701304

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.: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

May 10, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 15, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Long QT syndrome Uncertain:1

May 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 missense change has been observed in individual(s) with Long QT syndrome (PMID: 31941373). 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

-

Roden Lab, Vanderbilt University Medical Center

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
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	D
LIST_S2	Benign	0.80	.;.;T;.;.;.;.;.
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.4	M;M;M;M;M;M;M;M
PrimateAI	Uncertain	0.66	T
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	D
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

Other links and lift over

dbSNP: rs79654911; hg19: chr21-35821733;