ClinVar Miner

Submissions for variant NM_000218.2(KCNQ1):c.160_168dup (p.Ile54_Pro56dup) (rs397515877)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035343 SCV000058991 benign not specified 2017-05-18 criteria provided, single submitter clinical testing p.Ile54_Pro56dup in Exon 1 of KCNQ1: This variant is not expected to have clinic al significance because it has been identified in 2.9% (250/8370) of African ch romosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitu te.org; dbSNP rs561562768). It has been reported in two individuals with cardia c arrhythmias (1/182 LQTS, Berge 2008; 1/231 AF, Abraham 2010) and segregated in three affected individuals in one family, though phenotypes were unknown in 2 o ther mutation carriers (Abraham 2010). In addition, one study demonstrated some alteration of channel properties (Abraham 2010) although this study was only in vitro such that correlation to a clinical phenotype was not possible. This varia nt was also identified in several healthy control cohorts (0.3% 4/1488 chromosom es, Ackerman 2003; 1/364 chromosomes, Arnestad 2007; 2.1% (2/94) African-America n control chromosomes, Abraham 2010) and is now listed in the KCNQ1 database as a benign variant (http://www.fsm.it/cardmoc/kvlqt1poly.htm). In summary, given t he high frequency of the variant in spite of the reports in the literature, this variant is benign for a reasonably penetrant disease variant and insufficient b iological evidence for a clinically relevant impact to protein function, we have classified this variant as likely benign.
GeneDx RCV000035343 SCV000234378 likely benign not specified 2017-10-30 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001080143 SCV000259853 benign Long QT syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000250643 SCV000318444 uncertain significance Cardiovascular phenotype 2013-02-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000250643 SCV000318524 uncertain significance Cardiovascular phenotype 2013-03-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000035343 SCV000343643 benign not specified 2016-08-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586572 SCV000695987 likely benign not provided 2017-08-09 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852643 SCV000995348 likely benign Ventricular fibrillation 2019-05-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000035343 SCV001372409 likely benign not specified 2020-06-02 criteria provided, single submitter clinical testing Variant summary: KCNQ1 c.160_168dupATCGCGCCC (p.Ile54_Pro56dup) results in an in-frame duplication that is predicted to duplicate 3 amino acids into the encoded protein. The variant allele was found at a frequency of 0.0073 in 35616 control chromosomes, predominantly at a frequency of 0.03 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 300 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNQ1 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.160_168dupATCGCGCCC has been reported in the literature in individuals affected with Arrhythmia as well as in control population (e.g. Abraham_2010, Berge_2008, Ackerman_2003, Tester_2005_01, Kapa_2009, Hassnan_2017, Millat_2014). In a family with familial atrial fibrillation, this variant was found in four affected members and also in an unaffected carrier suggesting an inconclusive co-segregation of this variant with disease (Abraham_2010). This family however, was not comprehensively screened for mutations in all susceptibility genes. Co-occurrences with other pathogenic variants have been reported (KCNQ1 c.674C>T, p.Ser225Leu; KCNH2 c.1841C>T, p.Ala614Val) in our internal database. In vitro functional study detected partial defect of the channel properties (Abraham_2010), suggesting that it could be a functional polymorphism. Five ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=2) or benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
OMIM RCV000114749 SCV000148632 pathogenic Atrial fibrillation, familial, 3 2010-01-01 no assertion criteria provided literature only

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