rs1805128

Positions:

• chr21-34449382-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000219.6(KCNE1):​c.253G>A​(p.Asp85Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other,risk factor (no stars).

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNE1 NM_000219.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other; risk factor criteria provided, conflicting classifications P:2 U:2 B:14 O:5
• Conservation: PhyloP100: 2.98

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_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005815029).
• BP6: Variant 21-34449382-C-T is Benign according to our data. Variant chr21-34449382-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity, other, risk_factor]. Clinvar id is 13479.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, other=1, Likely_pathogenic=1, risk_factor=2, not_provided=2, Benign=7, Uncertain_significance=2, Pathogenic=1}. Variant chr21-34449382-C-T is described in Lovd as [Benign]. Variant chr21-34449382-C-T is described in Lovd as [Likely_pathogenic]. Variant chr21-34449382-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE1	NM_000219.6	c.253G>A	p.Asp85Asn	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.253G>A	p.Asp85Asn	missense_variant	4/4	1	NM_000219.6	ENSP00000382226	P1

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD3 exomes AF: 0.00944 AC: 2373 AN: 251426 Hom.: 20 AF XY: 0.00957 AC XY: 1300 AN XY: 135908

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.00549

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.00879

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1460688 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726712

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 17

Alfa AF: 0.0116 Hom.: 8

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0122 AC: 105

ExAC AF: 0.00914 AC: 1110

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0121

EpiControl AF: 0.0122

ClinVar

Significance: Conflicting classifications of pathogenicity; other; risk factor

Submissions summary: Pathogenic:2 Uncertain:2 Benign:14 Other:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4 Other:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:9445165;PMID:10807545;PMID:12402336;PMID:14661677;PMID:14760488;PMID:15051636;PMID:15599693;PMID:16132053;PMID:16266404;PMID:16487223;PMID:16887036;PMID:17016049;PMID:17161064;PMID:17210839;PMID:18426444;PMID:19695459;PMID:20823649;PMID:21244686;PMID:21712262;PMID:22100668;PMID:22378279). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 19019189, 32429735, 31447099, 31918855, 30384889, 17266934, 29874177, 28798025, 28003625, 29625280, 29540472, 27509294, 14760488, 24400172, 24561134, 19695459, 22999324, 20823649, 25119684, 16823764, 23237912, 23631430, 22995991, 21712262, 16132053, 22378279, 15051636, 22100668, 21244686, 17161064) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The KCNE1 p.D85N variant was identified in 93 of 4968 proband chromosomes (frequency: 0.0187) from individuals or families with Long QT syndrome (LQTS), however many of these individuals carried variants in other LQTS-related genes (Nishio_2009_PMID:19695459; Lahtinen_2011_PMID:21244686; Kaab_2012_PMID:22100668; Hasegawa_2014, Lane_2018_PMID:29625280). A 10 year old boy with LQTS was found to carry the KCNE1 p.D85N variant along with two other variants: KCNH2 p.N45D and SCN5A p.A1428S, 4282G>T; the proband's unaffected mother and unaffected aunt also carried the KCNE1 p.D85N variant (Yoshikane_2013_PMID:23237912). Another family was reported in which the LQTS-affected proband and daughter carried the KCNE1 p.D85N and KCNH2 p.E58K variants; the proband's unaffected eldest son carried the KCNH2 p.E58K variant and the unaffected youngest son carried the KCNE1 p.D85N variant (Hasegawa_2014). These findings suggest that the p.D85N variant may contribute to or modify disease but likely is not causal. Functional studies demonstrated that the KCNE1 p.D85N variant modified KCNQ1/KCNE1 currents, however this was attenuated when tested in conjunction with another LQTS-associated variant (Hasegawa_2014, Nishio_2009_PMID:19695459). The variant was identified in dbSNP (ID: rs1805128) and ClinVar (classified as benign by Invitae, EGL Genetics and three other laboratories, as likely benign by Laboratory for Molecular Medicine, Ambry Genetics and Illumina, as uncertain significance by Integrated Genetics and CeGaT Praxis fuer Humangenetik Tuebingen, as risk factor by Blueprint Genetics and Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine and as likely pathogenic by Medical Research Institute, Tokyo Medical and Dental University). The variant was identified in control databases in 2637 of 282814 chromosomes (22 homozygous) at a frequency of 0.009324 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 263 of 10368 chromosomes (freq: 0.02537), European (Finnish) in 424 of 25120 chromosomes (freq: 0.01688), European (non-Finnish) in 1580 of 129142 chromosomes (freq: 0.01223), Other in 65 of 7228 chromosomes (freq: 0.008993), East Asian in 111 of 19946 chromosomes (freq: 0.005565), Latino in 97 of 35438 chromosomes (freq: 0.002737), African in 54 of 24956 chromosomes (freq: 0.002164), and South Asian in 43 of 30616 chromosomes (freq: 0.001404). The p.D85 residue is conserved in mammals however four of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	KCNE1: BS1, BS2 -
other, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 24, 2017	- This variant is interpreted as a modifying variant which rises the succeptibility to develop LQTS. The variant has a pathogenic effect, but do not explain on it's own the development of LQTS.

Long QT syndrome Pathogenic:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2020	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely pathogenic, flagged submission	research	Medical Research Institute, Tokyo Medical and Dental University	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 01, 2022	- -

Jervell and Lange-Nielsen syndrome 2 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 15, 2018	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PP5,BS1,BP6. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 21, 2015	- -

Long QT syndrome 5 Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
risk factor, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 08, 2017	This c.253G>A (p.D85N) variant (rs1805128) in the KCNE1 gene is a potassium channel susceptibility allele for with diLQTS, defined as documented torsades de pointes during treatment with a QT-prolonging drug [PMID 22100668, 24400172, 22999324, 14760488, 21244686, 17161064]. The variant has also been associated with longer QT [PMID 16132053]. A previous study has shown to predict diLQTS with an odds ratio of 9.0 (95% confidence interval, 3.5–22.9) [PMID 22100668]. This variant is considered a risk allele for drug induced long QT. -

Congenital long QT syndrome Benign:1 Other:1

risk factor, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 04, 2020	KCNE1 c.253G>A (p.Asp85Asn) has been associated with increased risk for long QT syndrome. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of Ashkenazi Jewish ancestry (2.5%, Genome Aggregation Database (gnomAD); rs1805128) and is present in ClinVar (ID: 13479). Several studies have also reported an odds ratio of 4.2-8.9 for developing Long QT syndrome in heterozygous carriers of this variant (OR=8.88 [95% CI 3.26-24.17] Kaab 2011, OR=4.21 [95% CI 1.17-15.16] Gouas 2005). In vitro functional studies provide some evidence that this variant may impact protein function (Nishio 2009). In summary, this variant is a likely risk factor for Long QT syndrome. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Long QT syndrome 2/5, digenic Pathogenic:1

Pathogenic, flagged submission

literature only

OMIM

Aug 01, 2006

- -

Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

KCNE1 NM_000219.4 exon 4 p.Asp85Asn (c.253G>A): This variant has been reported in the literature in several individuals with LQTS and is reported to be overrepresented in this patient population compared to control individuals (Westenskow 2004 PMID:15051636, Nishio 2009 PMID:19695459, Kaab 2012 PMID:22100668, Weeke 2014 PMID:24561134, Maltese 2017 PMID:28003625, Lane 2018 PMID:29625280). Several authors in the literature suggest that this variant may act as a risk allele or modifying allele (Gouas 2005 PMID:16132053, Lahtinen 2011 PMID:21244686, Weeke 2014 PMID:24561134, Lane 2018 PMID:29625280). However, this variant is also present in 2.5% (263/10368) of Ashkenazi Jewish alleles in the Genome Aggregation Database, including 5 homozygotes (https://gnomad.broadinstitute.org/variant/21-35821680-C-T), suggesting that it may be a benign polymorphism. This variant is present in ClinVar (Variation ID:13479). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro functional studies do predict that this variant will impact the protein (Gouas 2005 PMID:16132053, Nishio 2009 PMID:19695459, Nof 2011 PMID:21712262, Du 2013 PMID:24400172). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 01, 2019

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Long QT syndrome 5, acquired, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;D;D;D;D;D;D;D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.68	.;.;T;.;.;.;.;.
MetaRNN	Benign	0.0058	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Uncertain	2.0	M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D;.;.;D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Benign	0.034	D;.;.;D;D;D;D;D
Sift4G	Benign	0.068	T;T;T;T;T;T;T;T
Polyphen		0.57	P;P;P;P;P;P;P;P
Vest4		0.22
MVP		0.89
MPC		0.19
ClinPred		0.038	T
GERP RS		4.2
Varity_R		0.16
gMVP		0.84

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: rs1805128; hg19: chr21-35821680; COSMIC: COSV104640789;