ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.798G>T (p.Lys266Asn) (rs12720457)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000057570 SCV000604064 likely benign not provided 2017-05-26 criteria provided, single submitter clinical testing The p.Lys393Asn variant (rs12720457; c.1179G>T or c.1179G>C) has been reported in cohorts of long QT syndrome/sudden infant death syndrome (SIDS) patients (Crotti 2013 and Giudicessi 2012), but has also been reported in multiple control populations (Arnestad 2007, Kapa 2009, Ghouse 2015). Moreover, in the Ghouse (2015) study, there was no significant difference in measured length of QT interval between carriers of the p.Lys393Asn variant and non-carriers, and functional analysis of p.Lys393Asn suggests this variant has no impact on KCNQ1 channel function (Shamgar 2006). The c.1179G>T variant is also listed in the ClinVar database as benign or likely benign (Variation ID: 67020), and is found in the general population as listed in the NHLBI GO Exome Sequencing Project (ESP) with an overall allele frequency of 0.07% (identified in 9 out of 13,000 chromosomes), and in the Exome Aggregation Consortium (ExAC) browser with an overall frequency of 0.11% (identified in 133 out of 121,176 chromosomes). Therefore, the c.1179G>T; p.Lys393Asn variant is likely to be benign.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148543 SCV000050828 benign Long QT syndrome 2013-06-24 criteria provided, single submitter research
CSER_CC_NCGL; University of Washington Medical Center RCV000148543 SCV000190256 likely benign Long QT syndrome 2014-06-01 no assertion criteria provided research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057570 SCV000089089 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:14661677;PMID:14678125;PMID:17161064;PMID:17210839;PMID:17470695;PMID:19841300;PMID:19862833).
Color RCV000776184 SCV000911310 likely benign Arrhythmia 2018-03-16 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000057570 SCV000232929 uncertain significance not provided 2015-01-16 criteria provided, single submitter clinical testing
GeneDx RCV000154657 SCV000234375 likely benign not specified 2016-06-20 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.
Illumina Clinical Services Laboratory,Illumina RCV000394039 SCV000370275 likely benign Romano-Ward syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000306809 SCV000370276 likely benign Jervell and Lange-Nielsen syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000148543 SCV000370277 likely benign Long QT syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000394030 SCV000370278 likely benign short QT syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000305127 SCV000370279 likely benign Familial atrial fibrillation 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000154657 SCV000919556 likely benign not specified 2017-10-16 criteria provided, single submitter clinical testing Variant summary: The KCNQ1 c.1179G>T (p.Lys393Asn) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 292/277174 control chromosomes, including 1 homozygous individual, predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.00266 (27/10152). This frequency is about 27 times the estimated maximal expected allele frequency of a pathogenic KCNQ1 variant (0.0001), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.
Invitae RCV000148543 SCV000555803 benign Long QT syndrome 2017-06-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154657 SCV000204333 likely benign not specified 2017-07-20 criteria provided, single submitter clinical testing p.Lys393Asn in exon 9 of KCNQ1: This variant is not expected to have clinical si gnificance because it has been reported in the literature in both control and cl inical cohorts (Ackerman 2003, Moss 2007, Guidicessi 2012, Crotti 2013). In addi tion, this variant has been identified in 0.3% (27/10152) of Ashkenazi Jewish ch romosomes and 0.2% (52/30782) of South Asian chromosomes including 1 homozygote by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; db SNP rs12720457). Studies have shown that the p.Lys393Asn variant does not impact protein function (Shamgar 2006). Furthermore, the lysine (Lys) at amino acid po sition 393 is not conserved across species, including mammals. Of note, cat has an asparagine (Asn) at this position despite high nearby amino acid conservation . Additional computational analyses do not suggest a high likelihood of impact t o the protein. In summary, this variant is classified as likely benign based on the available data.

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