ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.436C>T (p.Leu146Phe) (rs120074180)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182120 SCV000234423 pathogenic not provided 2018-07-13 criteria provided, single submitter clinical testing The L273F variant (aka L144F due to alternative nomenclature) in the KCNQ1 gene has been reported previously in association with LQTS and it was absent from more than 1,500 control alleles (Wang Q et al., 1996; Huang L et al., 2001; Tester D et al., 2005). In addition, the L273F variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Several functional studies have reported the Leu273Phe variant significantly alters potassium ion channel function (Shalaby F et al., 1997; Seebohm G et al., 2001; Peretz 2002; Gibor G et al., 2007). A different variant at the same residue (L273R) as well as variants in nearby residues (T265I, G272V, F275S, S277P) have been reported in association with LQTS, further supporting the functional importance of this residue and this region of the protein.
Ambry Genetics RCV000620696 SCV000737700 pathogenic Cardiovascular phenotype 2018-07-12 criteria provided, single submitter clinical testing Strong segregation with disease (lod >3 = >10 meioses);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Integrated Genetics/Laboratory Corporation of America RCV001192509 SCV001360696 pathogenic Long QT syndrome 2019-05-06 criteria provided, single submitter clinical testing Variant summary: KCNQ1 c.817C>T (p.Leu273Phe) results in a non-conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250444 control chromosomes. c.817C>T has been reported in the literature in multiple individuals and families affected with Long QT Syndrome (Kharbanda_2017, Wang_1996, Burns_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. This report shows that the variant displays a pronounced KCNQ1 inactivation (Seebohm_2001). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000003266 SCV000023424 pathogenic Long QT syndrome 1 1996-01-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057769 SCV000089288 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:8528244;PMID:9323054;PMID:10973849;PMID:11216980;PMID:14678125;PMID:15840476;PMID:16922724;PMID:16937190;PMID:19716085;PMID:19841300;PMID:17470695;PMID:15935335;PMID:11278406). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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