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rs1805128

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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). Synonymous variant affecting the same amino acid position (i.e. D85D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 17)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

KCNE1
NM_000219.6 missense

Scores

1
7
9

Clinical Significance

Conflicting classifications of pathogenicity; other; risk factor criteria provided, conflicting classifications P:2U:2B:14O:5

Conservation

PhyloP100: 2.98
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 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: {risk_factor=2, Benign=7, Likely_benign=6, Uncertain_significance=2, not_provided=1, other=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].
BS2
High Homozygotes in GnomAdExome at 20 AD,AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNE1NM_000219.6 linkuse as main transcriptc.253G>A p.Asp85Asn missense_variant 4/4 ENST00000399286.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNE1ENST00000399286.3 linkuse as main transcriptc.253G>A p.Asp85Asn missense_variant 4/41 NM_000219.6 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
show subpopulations
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:2Uncertain:2Benign:14Other:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:4Other:2
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024KCNE1: BS1, BS2 -
not provided, no classification providedliterature onlyCardiovascular 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). -
Likely benign, no assertion criteria providedclinical testingDepartment 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 submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
other, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteJul 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.
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This 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) -
Long QT syndrome Pathogenic:1Benign:3
Likely benign, criteria provided, single submitterclinical testingBlueprint GeneticsNov 01, 2022- -
Benign, criteria provided, single submitterclinical testingInvitaeDec 07, 2020- -
Benign, criteria provided, single submitterresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJun 24, 2013- -
Likely pathogenic, no assertion criteria providedresearchMedical Research Institute, Tokyo Medical and Dental University-- -
Jervell and Lange-Nielsen syndrome 2 Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaOct 15, 2018This 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 25, 2023- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Sep 21, 2015- -
Long QT syndrome 5 Benign:1Other:1
risk factor, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineJun 08, 2017This 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. -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
Congenital long QT syndrome Benign:1Other:1
risk factor, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 04, 2020KCNE1 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 submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Long QT syndrome 2/5, digenic Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 01, 2006- -
Long QT syndrome 5;C2676723:Jervell and Lange-Nielsen syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021KCNE1 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 submitterclinical testingCenter for Advanced Laboratory Medicine, UC San Diego Health, University of California San DiegoApr 01, 2019- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 25, 2018This 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 providedliterature onlyOMIMAug 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
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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