chr21-34449462-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_000219.6(KCNE1):c.173C>T(p.Thr58Ile) variant causes a missense change. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T58S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 17)

Exomes 𝑓: 0.0000053 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNE1
NM_000219.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4

Conservation

PhyloP100: 6.68

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

long QT syndrome 5
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Jervell and Lange-Nielsen syndrome 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
Jervell and Lange-Nielsen syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
atrial fibrillation
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

KCNE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP5

Variant 21-34449462-G-A is Pathogenic according to our data. Variant chr21-34449462-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372392.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNE1	NM_000219.6 link	c.173C>T	p.Thr58Ile	missense_variant	Exon 4 of 4	ENST00000399286.3	NP_000210.2	P15382C7S316Q6FHJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNE1	ENST00000399286.3 link	c.173C>T	p.Thr58Ile	missense_variant	Exon 4 of 4	1	NM_000219.6	ENSP00000382226.2		P15382

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

115418

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251410

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000526

AC:

AN:

1141764

Hom.:

Cov.:

AF XY:

0.00000346

AC XY:

AN XY:

578700

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26450

American (AMR)

AF:

0.000120

AC:

AN:

41746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23652

East Asian (EAS)

AF:

0.0000272

AC:

AN:

36738

South Asian (SAS)

AF:

0.00

AC:

AN:

77430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51820

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5252

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

828960

Other (OTH)

AF:

0.00

AC:

AN:

49716

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0772119), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

115418

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

55534

African (AFR)

AF:

0.00

AC:

AN:

30202

American (AMR)

AF:

0.00

AC:

AN:

11568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2658

East Asian (EAS)

AF:

0.00

AC:

AN:

3526

South Asian (SAS)

AF:

0.00

AC:

AN:

3278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

244

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53362

Other (OTH)

AF:

0.00

AC:

AN:

1546

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Aug 16, 2016

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The T58I variant that is likely pathogenic was identified in the KCNE1 gene. It has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge.However, this variant has been reported in one other individual referred for LQTS genetic testing atGeneDx. The T58I variant was not observed in approximately 6,500 individuals of European andAfrican American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a commonbenign variant in these populations. The T58I variant is a non-conservative amino acid substitution,which is likely to impact secondary protein structure as these residues differ in polarity, charge, sizeand/or other properties, and this substitution occurs at a position that is conserved across species. Alikely pathogenic variant at the same residue (T58P) has been reported in the Human Gene MutationDatabase in association with LQTS (Stenson et al., 2014), supporting the functional importance ofthis residue. Furthermore, functional studies of the KCNE1 gene by Melman et al. (2002) concludedthat T58, the central amino acid of a triplet responsible for the specificity of KCNE1 control ofactivation of the potassium channel, is essential for the specific control of voltage-dependent channelactivation characteristics. However, in silico analysis is inconsistent in its predictions as to whether ornot the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic. -

Primary dilated cardiomyopathy

Pathogenic:1

Aug 29, 2017

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

May 02, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The KCNE1 c.173C>T; p.Thr58Ile variant (rs747321794) is reported in the literature in at least one individual affected with long QT syndrome (Faridi 2019). Additionally, another variant at this codon (c.172A>C; p.Thr58Pro) has been reported in individuals with long QT syndrome (Kapplinger 2009). The p.Thr58Ile variant is reported in ClinVar (Variation ID: 372392), and is found in the Latino population with an allele frequency of 0.023% (8/35,440 alleles) in the Genome Aggregation Database. The threonine at codon 58 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: probably damaging) predict conflicting effects of this variant on protein structure/function. However, functional analyses of the KCNE1 protein show that threonine 58 is critical for specific control of the voltage-dependent potassium channel, and that the p.Thr58Ile variant results in voltage-independent activation in vitro (Melman 2002). Due to limited information, the clinical significance of the p.Thr58Ile variant is uncertain at this time. References: Faridi R et al. Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange-Nielsen Syndrome and Romano-Ward Syndrome. Hum Mutat. 2019 Feb;40(2):162-176. Kapplinger JD et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. Melman YF et al. A single transmembrane site in the KCNE-encoded proteins controls the specificity of KvLQT1 channel gating. J Biol Chem. 2002 Jul 12;277(28):25187-94. -

SUDDEN INFANT DEATH SYNDROME

Uncertain:1

Oct 01, 2021

Robert's Program, Boston Children's Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

We classify this variant as a variant of uncertain significance using ACMG/AMP criteria. As this variant has functional evidence supporting pathogenicty, we suspect this variant is favoring pathogenic. -

Long QT syndrome

Uncertain:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 58 of the KCNE1 protein (p.Thr58Ile). This variant is present in population databases (rs747321794, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 30461122). ClinVar contains an entry for this variant (Variation ID: 372392). Invitae Evidence 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 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. 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. -

Cardiovascular phenotype

Uncertain:1

Aug 08, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T58I variant (also known as c.173C>T), located in coding exon 1 of the KCNE1 gene, results from a C to T substitution at nucleotide position 173. The threonine at codon 58 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in a long QT syndrome cohort and a sudden unexplained death cohort; however, clinical details were limited in both cases (Faridi R et al. Hum Mutat, 2019 Feb;40:162-176; Koh HY et al. Genet Med, 2022 Apr;24:839-850). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

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

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.83

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

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.59

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

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.8

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

PhyloP100

6.7

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.2

N;.;.;N;N;N;N;N

REVEL

Uncertain

0.55

Sift

Benign

0.20

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

Sift4G

Benign

0.12

T;T;T;T;T;T;T;T

Polyphen

1.0

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

Vest4

0.62

MutPred

0.25

Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);

MVP

0.93

MPC

0.45

ClinPred

0.89

GERP RS

5.2

Varity_R

0.34

gMVP

0.88

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over