21-34449409-C-T

Position:

chr21-34449409-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong

The ENST00000399286.3(KCNE1):c.226G>A(p.Asp76Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,598,798 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D76A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000056 ( 0 hom., cov: 17)

Exomes 𝑓: 0.00013 ( 3 hom. )

Consequence

KCNE1
ENST00000399286.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21U:1O:2

Conservation

PhyloP100: 5.04

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.785

PP5

Variant 21-34449409-C-T is Pathogenic according to our data. Variant chr21-34449409-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-34449409-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNE1	NM_000219.6 linkuse as main transcript	c.226G>A	p.Asp76Asn	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 linkuse as main transcript	c.226G>A	p.Asp76Asn	missense_variant	4/4	1	NM_000219.6	ENSP00000382226	P1

Frequencies

GnomAD3 genomes

AF:

0.0000565

AC:

AN:

141658

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000520

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:

0.0000934

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251386

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000128

AC:

187

AN:

1457140

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

725178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000160

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000565

AC:

AN:

141658

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

68600

show subpopulations

Gnomad4 AFR

AF:

0.0000520

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000934

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21Uncertain:1Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 24, 2020	The KCNE1 c.226G>A; p.Asp76Asn variant (rs74315445) is reported in the literature in multiple individuals affected with long QT syndrome (Christiansen 2014, Kapplinger 2009, Splawski 1997, Tester 2005). In addition, this variant was found in the homozygous or compound heterozygous state in several families with Jervell and Lange-Nielsen syndrome and was found to segregate with disease (Duggal 1998, Schulze-Bahr 1997). This variant is found in the non-Finnish European population with an overall allele frequency of 0.01% (14/129102 alleles) in the Genome Aggregation Database. The aspartate at codon 76 is highly conserved, and functional studies suggest this variant leads to altered potassium channel activity, including reduced current and faster deactivation (Kurokawa 2003, Splawski 1997). Based on available information, this variant is considered to be likely pathogenic. References: Christiansen M et al. Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2. BMC Med Genet. 2014;15:31. Duggal P et al. Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of Long-QT syndrome. Circulation. 1998;97(2):142-146. Kapplinger JD 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;6(9):1297-1303. Kurokawa J et al. Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel. Proc Natl Acad Sci U S A. 2003;100(4):2122-2127. Schulze-Bahr E et al. KCNE1 mutations cause Jervell and Lange-Nielsen syndrome. Nat Genet. 1997;17(3):267-268. Splawski I et al. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet. 1997;17(3):338-340. Tester DJ et al. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005;2(5):507-517. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2022	Published functional studies demonstrate a damaging effect as this variant leads to a dominant-negative loss of channel function (Splawski et al., 1997; Hoppe et al., 2001; Chen et al., 2009; Du et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9354783, 19695459, 30461122, 30609406, 32344329, 16914890, 20196769, 9354802, 10428953, 11874988, 12566567, 24400172, 24606995, 25637381, 11320260, 19340287, 24478792, 10400998, 24561134, 26410412, 26926294, 15840476, 19716085, 26187847, 27807201, 9445165, 30930557, 23631430, 23124029, 19521339, 31835641, 31941373, 31737537, 31447099, 32058015, 30847666) -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 27, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Long QT syndrome 5

Pathogenic:5Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 20, 1998	- -
not provided, no classification provided	in vitro	Roden Lab, Vanderbilt University Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic with reduced penetrance. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Jervell and Lange-Nielsen syndrome 2 (MIM#612347) and long QT syndrome 5 (MIM#613695) (PMID: 31941373). This gene has limited evidence for association with long QT syndrome, however it has strong evidence for the association with acquired long QT syndrome (PanelApp Australia, PMIDs: 31983240, 35373836). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic and monoallelic variants in this gene have been associated with Jervell and Lange-Nielsen syndrome 2 (MIM#612347) and long QT syndrome 5 (MIM#613695), respectively. This gene has limited evidence for association with long QT syndrome, however it has strong evidence for the association with acquired long QT syndrome (PanelApp Australia, PMIDs: 31983240, 35373836). (I) 0112 - The condition associated with this gene has incomplete penetrance. Weak penetrance has been reported for KCNE1 variants associated with long QT syndrome (PMID: 31941373). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3: 26 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ISK channel domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has frequently been reported as likely pathogenic/pathogenic, and in many individuals with long QT syndrome (ClinVar, VCGS, PMIDs: 32058015, 31941373). However it has also been reported in individuals who remained asymptomatic lifelong (PMID: 32058015). It is a weakly penetrant variant that rarely causes potentially lethal ventricular arrhythmias in the absence of additional genetic and/or acquired risk factors (PMID: 32058015). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies using patch clamp technique showed reduced potassium current and accelerated channel deactivation rates in multiple cell types with the variant (PMIDs: 9354802, 19340287, 24400172). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 16, 2017	This c.226G>A (p.Asp76Asn) variant in the KCNE1 gene has been reported in multiple unrelated individuals with Long QT syndrome (LQTS; PMID: 15840476, 19716085, 24606995) and has been shown in families to segregate with the LQTS phenotype (PMID: 9354802). It has also been reported in the homozygous or compound heterozygous state in individuals with Jervell and Lange-Nielsen syndrome, with some heterozygous family members manifesting features of LQTS (PMID: 9354783, 9445165). The c.226G>A variant is rare in the general population. Functional studies have indicated that the p.Asp76Asn variant KCNE1 protein has altered activity (PMID: 10400998, 10428953, 11874988, 12566567). The c.226G>A (p.Asp76Asn) variant in the KCNE1 gene is classified as likely pathogenic. -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jan 08, 2015	The heterozygous variant in the KCNE1 gene (c.226G>A; p.Asp76Asn) is considered a likely pathogenic variant. This amino acid position is well conserved and the change is non-conservative while the nucleotide is only moderately conserved. The same change has been seen in 4 individuals of European origin in the ExAC database out of 121246 alleles interrogated at this position. This variant has been initially published by Schulze-Bahr et al (PMID: 9354783) in one family with Jervell and Lange-Nielsen syndrome in 3 affected siblings, it has been published in 9 individuals with Long QT by Kapplinger et al. (PMID: 19716085). Available functional studies in Xenopus laevis oocytes and in Chinese hamster ovaries indicate a reduced function for this variant relative to wild type (PMID: 11874988, 12566567). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jul 05, 2021	- -

Long QT syndrome

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 08, 2019	This c.226G>A (p.Asp76Asn) variant in the KCNE1 gene has been reported in multiple unrelated individuals with Long QT syndrome (LQTS; PMID: 15840476, 19716085, 24606995) and has been shown in families to segregate with the LQTS phenotype (PMID: 9354802). It has also been reported in the homozygous or compound heterozygous state in individuals with Jervell and Lange-Nielsen syndrome, with some heterozygous family members manifesting features of LQTS (PMID: 9354783, 9445165). The c.226G>A variant is rare in the general population having been seen in 19/282776 alleles in the gnomAD population database. Functional studies have indicated that the p.Asp76Asn variant KCNE1 protein has altered activity (PMID: 10400998, 10428953, 11874988, 12566567). The c.226G>A (p.Asp76Asn) variant in the KCNE1 gene is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Dec 22, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PS3_Moderate, PM1, PP1, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 76 of the KCNE1 protein (p.Asp76Asn). This variant is present in population databases (rs74315445, gnomAD 0.01%). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome (JLNS) and long QT syndrome (PMID: 9354783, 9354802, 9445165, 19716085, 24561134, 24606995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13477). 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. Experimental studies have shown that this missense change affects KCNE1 function (PMID: 9354802, 10400998, 10428953, 11874988, 12566567, 24400172). For these reasons, this variant has been classified as Pathogenic. -

Congenital long QT syndrome

Pathogenic:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 13, 2018	The p.Asp76Asn variant in KCNE1 (ClinVar variation ID# 13477) has been reported in the heterozygous state in at least 18 individuals with Long QT syndrome (LQTS ; Splawski 1997, Duggal 1998, Tester 2005, Tester 2006, Kapplinger 2009, Christi ansen 2014, Weeke 2014, Li 2015) as well as one affected relative (Splawski 1997 ). This variant has also been identified in 14/126618 European chromosomes by th e Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). This f requency is high given the prevalence of LQTS (Orphanet: ~1/2,500 individuals) a nd genetic heterogeneity of the disease but does not rule out pathogenicity as L QTS is known to have clinical variability and reduced penetrance. A pathogenic role is supported by two families with Jervell and Lange-Nielsen syndrome (JLNS) , which includes prolonged QT as one of several features. In one family, the va riant was present in the compound heterozygous state in three affected siblings (Schulze-Bar 1997). I the other family, the proband was homozygous for the p.As p76Asn variant and two heterozygous family members were reported to have LQTS (D uggal 1998). In vitro functional studies provide some evidence that the p.Asp76A sn variant may impact protein function (Splawski 1997, Kurokawa 2003, Seebohm 20 08, Haitin 2009, Chen 2009, Du 2013). However, these types of assays may not acc urately represent biological function. In vivo studies in guinea-pigs have shown that this variant affects cardiac repolarization in myocytes (Hoppe 2001). Comp utational prediction tools and conservation analysis do not provide strong suppo rt for or against an impact to the protein. In summary, this variant meets crite ria to be classified as likely pathogenic for LQTS in an autosomal dominant mann er and for JLNS in an autosomal recessive manner based upon segregation studies and functional evidence. ACMG/AMP Criteria applied: ACMG/AMP criteria applied: P M3, PS3_Moderate, PP1_Moderate. -
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:9354783;PMID:9354802;PMID:9445165;PMID:15840476;PMID:16818210;PMID:19716085;PMID:9328483;PMID:11874988). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

not specified

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Aug 01, 2017

- -

Jervell and Lange-Nielsen syndrome 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Jervell and Lange-Nielsen syndrome 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 20, 1998

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2020

The p.D76N pathogenic mutation (also known as c.226G>A), located in coding exon 1 of the KCNE1 gene, results from a G to A substitution at nucleotide position 226. The aspartic acid at codon 76 is replaced by asparagine, an amino acid with highly similar properties. This mutation has been reported in multiple unrelated individuals with long QT syndrome (Lieve KV et al. Genet Test Mol Biomarkers 2013; 17(7):553-61; Kapplinger JD et al. Heart Rhythm 2009; 6(9):1297-303; Tester DJ et al. Heart Rhythm 2005; 2(5):507-17; Splawski I et al. Circulation 2000; 102(10):1178-85) and segregated with disease in two individuals with long QT syndrome in a family (Splawski I et al. Nat. Genet. 1997; 17(3):338-40). The alteration has been reported in compound heterozygosity with a second KCNE1 variant in siblings with Jervell and Lange-Nielsen syndrome (Schulze-Bahr E et al. Nat. Genet. 1997; 17(3):267-8). This variant has also been detected in the homozygous state in an individual with Jervell and Lange-Nielsen syndrome whose heterozygous family members had phenotypes consistent with long QT syndrome (Duggal P et al. Circulation 1998; 97(2):142-6). This variant has been reported to exhibit reduced penetrance in cohorts (Roberts JD et al. Circulation. 2020 02;141(6):429-439). In vitro assays have reported that the p.D76N alteration impairs ion channel function by altering voltage dependence and suppressing current through KCNQ1 and KCNH2-associated channels (Kurokawa J et al. Proc. Natl. Acad. Sci. U.S.A. 2003; 100(4):2122-7; Abbott GW et al. FASEB J. 2002; 16(3):390-400; Bianchi L et al. Hum. Mol. Genet. 1999; 8(8):1499-507). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. However, pathogenic and likely pathogenic KCNE1 variants typically exhibit low penetrance in the heterozygous state and may represent risk factors that manifest clinically only in the presence of additional genetic or environmental factors (Roberts JD et al. Circulation. 2020 02;141(6):429-439). -

Jervell and Lange-Nielsen syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 13, 2018

The p.Asp76Asn variant in KCNE1 (ClinVar variation ID# 13477) has been reported in the heterozygous state in at least 18 individuals with Long QT syndrome (LQTS ; Splawski 1997, Duggal 1998, Tester 2005, Tester 2006, Kapplinger 2009, Christi ansen 2014, Weeke 2014, Li 2015) as well as one affected relative (Splawski 1997 ). This variant has also been identified in 14/126618 European chromosomes by th e Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). This f requency is high given the prevalence of LQTS (Orphanet: ~1/2,500 individuals) a nd genetic heterogeneity of the disease but does not rule out pathogenicity as L QTS is known to have clinical variability and reduced penetrance. A pathogenic role is supported by two families with Jervell and Lange-Nielsen syndrome (JLNS) , which includes prolonged QT as one of several features. In one family, the va riant was present in the compound heterozygous state in three affected siblings (Schulze-Bar 1997). I the other family, the proband was homozygous for the p.As p76Asn variant and two heterozygous family members were reported to have LQTS (D uggal 1998). In vitro functional studies provide some evidence that the p.Asp76A sn variant may impact protein function (Splawski 1997, Kurokawa 2003, Seebohm 20 08, Haitin 2009, Chen 2009, Du 2013). However, these types of assays may not acc urately represent biological function. In vivo studies in guinea-pigs have shown that this variant affects cardiac repolarization in myocytes (Hoppe 2001). Comp utational prediction tools and conservation analysis do not provide strong suppo rt for or against an impact to the protein. In summary, this variant meets crite ria to be classified as likely pathogenic for LQTS in an autosomal dominant mann er and for JLNS in an autosomal recessive manner based upon segregation studies and functional evidence. ACMG/AMP Criteria applied: ACMG/AMP criteria applied: P M3, PS3_Moderate, PP1_Moderate. -

Arrhythmogenic right ventricular cardiomyopathy;C0520806:Sudden unexplained death;C1142166:Brugada syndrome

Uncertain:1

Uncertain significance, flagged submission

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 14, 2017

The KCNE1 Asp76Asn variant has been reported in several cases of long QT syndrome and was absent from >2000 controls, collectively (Kapplinger JD, et al., 2009; Tester DJ, et al., 2005; Duggal P, et al., 1998; Splawski I, et al., 1997). It has also been reported in 1 case of CPVT (Tester DJ, et al., 2006), 2 cases of Jervell and Lange-Neilson Syndrome (Schulze-Bahr E, et al., 1997; Duggal P, et al., 1998) and 2 cases of sudden cardiac arrest/death (Li MH, et al., 2015). The homozygous case reported in Duggal P et al. (1998) expressed a severe phenotype, compared to the compound heterozygous family in Schulze-Bahr E et al. (1997). The variant is absent from the 1000 genomes project (http://www.1000genomes.org/) and present at low frequency in the Exome Aggregation Consortium dataset (MAF= 0.000033; http://exac.broadinstitute.org/). This frequency is higher than expected given the absolute rarity of LQT5. We identified this variant in a young proband that presented with sudden cardiac death with suggested evidence of ARVC and family history of Brugada syndrome. After extensive clinical evaluation there are no individuals with a demonstrated prolonged QT, and the variant does not segregate with the phenotype of Brugada/ARVC. Computational tools MutationTaster and PolyPhen-2 predict this variant to be "disease-causing" and "probably damaging" respectively, however SIFT predicts this variant to be "tolerated". Functional studies in frog oocytes have shown that the variant results in functional consequences such as delayed cardiac repolarization and increased risk of arrhythmia's (Splawski I, et al., 1997) and negatively affects the function of potassium channels (Kurokawa J, et al., 2013; Abbott GW and Goldstein SA, 2002). In summary, based on these conflicting interpretations, we classify KCNE1 Asp76Asn as a variant of "uncertain significance". -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

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

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

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

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.78

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

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.4

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

MutationTaster

Benign

0.97

A;A;A;A;A;A;A;A;A;A;A;A

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.7

D;.;.;D;D;D;D;D

REVEL

Uncertain

0.62

Sift

Benign

0.086

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.98

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

Vest4

0.59

MVP

0.96

MPC

0.37

ClinPred

0.49

GERP RS

5.2

Varity_R

0.20

gMVP

0.85

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over