ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.533G>C (p.Trp178Ser) (rs120074186)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182130 SCV000234433 pathogenic not provided 2018-12-20 criteria provided, single submitter clinical testing The W305S pathogenic variant in the KCNQ1 gene has been reported in association with both Jervell and Lange-Nielsen syndrome type-1 (JLNS1) and LQTS (Neyroud et al., 1997; Neyroud et al., 1998; Tester et al., 2005; Jons et al., 2009; Kapplinger et al., 2009; Barsheshet et al., 2012; Crotti et al., 2012). Neyroud et al. (1997, 1998) identified W305S in the homozygous state in at least three individuals with JLNS1 from two unrelated, consanguineous families; the heterozygous parents in both families were reportedly unaffected. The W305S variant has also been identified in the heterozygous state, independent of additional cardiogenetic variants, in at least three unrelated individuals with LQTS referred for genetic testing at GeneDx. W305S is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant results in a non-conservative amino acid substitution, and in silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, functional studies by Chouabe et al. (1997) demonstrate that W305S expressed in the homozygous state results in a complete loss of function of the potassium channel, while W305S expressed in conjunction with the wild-type channel results in reduced potassium channel current. Lastly, different pathogenic or likely pathogenic missense variants affecting the same residue (W305L) or nearby residues (A302E, A302V, W304R, W304L, G306R, V307M, V310I) have been reported in the Human Gene Mutation Database and/or at GeneDx in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein. In summary, W305S in the KCNQ1 gene is interpreted as a pathogenic variant.
Ambry Genetics RCV000622153 SCV000738133 likely pathogenic Cardiovascular phenotype 2018-02-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Structural Evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
OMIM RCV000003275 SCV000023433 pathogenic Jervell and Lange-Nielsen syndrome 1 1998-03-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057796 SCV000089315 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:9781056;PMID:15840476;PMID:19716085;PMID:9312006;PMID:17999538). 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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