ClinVar Miner

Submissions for variant NM_000219.6(KCNE1):c.226G>A (p.Asp76Asn) (rs74315445)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000222568 SCV000278993 pathogenic not provided 2018-09-14 criteria provided, single submitter clinical testing The D76N pathogenic variant in the KCNE1 gene has been reported in multiple individuals in association with LQTS (Tester et al., 2005; Kapplinger et al., 2009; Christiansen et al., 2014), and had been observed in multiple probands with LQTS referred for genetic testing at GeneDx. This variant has been shown to segregate with a prolonged QT interval in multiple affected heterozygous relatives from unrelated families, as reported by Duggal et al. (1998) and observed at GeneDx. Additionally, this variant has been reported in individuals with JLNS in both the homozygous state, and in the compound heterozygous state with a second KCNE1 variant (Schulze-Bahr et al., 1997; Duggal et al., 1998). This variant is observed at a low frequency of 14/126618 (0.01%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The D76N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, several functional studies support that D76N 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).
Ambry Genetics RCV000243273 SCV000319991 pathogenic Cardiovascular phenotype 2017-11-30 criteria provided, single submitter clinical testing 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). 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, p.D76N is interpreted as a disease-causing mutation.
Invitae RCV000471399 SCV000549148 pathogenic Long QT syndrome 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 76 of the KCNE1 protein (p.Asp76Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs74315445, ExAC <0.01%). This variant has been reported to segregate with Jervell and Lange-Nielsen syndrome (JLNS) and long QT syndrome in two families (PMID: 9354783, 9354802). It has also been reported in unrelated individuals affected with long QT syndrome (PMID: 24561134, 24606995, 19716085) and JLNS (PMID: 9445165). ClinVar contains an entry for this variant (Variation ID: 13477). Experimental studies have shown that this variant reduces current density accelerating channel deactivation (PMID: 10428953, 24400172, 12566567, 11874988, 9354802, 10400998). For these reasons, this variant has been classified as Pathogenic.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000584826 SCV000692512 uncertain significance Arrhythmogenic right ventricular cardiomyopathy; Brugada syndrome; Sudden unexplained death 2017-03-14 criteria provided, single submitter research 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".
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000606753 SCV000711385 likely pathogenic Jervell and Lange-Nielsen syndrome 2018-07-13 criteria provided, single submitter clinical testing 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000119080 SCV000711386 likely pathogenic Congenital long QT syndrome 2018-07-13 criteria provided, single submitter clinical testing 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000014420 SCV000839962 likely pathogenic Long QT syndrome 5 2017-10-16 criteria provided, single submitter clinical testing 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000471399 SCV000987324 pathogenic Long QT syndrome 2016-12-22 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000222568 SCV001246782 pathogenic not provided 2018-07-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287665 SCV001474376 likely pathogenic none provided 2020-07-24 criteria provided, single submitter clinical testing 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.
OMIM RCV000014419 SCV000034668 pathogenic Jervell and Lange-Nielsen syndrome 2 1998-01-20 no assertion criteria provided literature only
OMIM RCV000014420 SCV000034669 pathogenic Long QT syndrome 5 1998-01-20 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000119080 SCV000153799 not provided Congenital long QT syndrome no assertion provided literature only 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.
CSER _CC_NCGL, University of Washington RCV000148512 SCV000190224 likely pathogenic Jervell and Lange-Nielsen syndrome 1 2014-06-01 no assertion criteria provided research
Division of Human Genetics,Children's Hospital of Philadelphia RCV000014420 SCV000238442 likely pathogenic Long QT syndrome 5 2015-01-08 no assertion criteria provided research 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).
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678806 SCV000804988 likely pathogenic not specified 2017-08-01 no assertion criteria provided clinical testing

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