ClinVar Miner

Submissions for variant NM_000218.2(KCNQ1):c.532G>A (p.Ala178Thr) (rs120074177)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000244422 SCV000320309 likely pathogenic Cardiovascular phenotype 2015-09-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position
CSER_CC_NCGL; University of Washington Medical Center RCV000148553 SCV000190266 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057692 SCV000089211 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:9024139;PMID:19716085;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000182081 SCV000234384 pathogenic not provided 2017-05-02 criteria provided, single submitter clinical testing The A178T pathogenic variant in the KCNQ1 gene has been published previously in association with LQTS (Tanaka et al., 1997; Splawski et al., 2000; Kapplinger et al., 2009). Tanaka et al. (1997) identified A178T (reported as A49T due to alternative nomenclature) to segregate with LQTS in one Japanese family. The A178T variant results in a non-conservative amino acid substitution of a non-polar alanine residue with a polar threonine residue between the S2-S3 transmembrane domains at a residue that is conserved across species. Functional studies show that the A178T mutation severely disrupted channel trafficking (Harmer et al., 2014). Another variant affecting this same residue (A178P) and neighboring residues (R174C, R174H, R174P, R174L, G179S) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this region of the protein. Finally, the A178T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000148553 SCV000074088 pathogenic Long QT syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 178 of the KCNQ1 protein (p.Ala178Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs120074177, ExAC <0.01%). This variant has been reported in three individuals affected with longQT syndrome (PMID: 9024139, 22456477, 10973849) and in one patient referred to longQT genetic testing (PMID: 19716085). This variant is also known in the literature as A49T. ClinVar contains an entry for this variant (Variation ID: 53061). One experimental study has shown that this missense variant moderately reduces current density, peak tail current density, and shifts the voltage dependent of channel activation in vitro (PMID: 24912595). A different missense substitution at this codon (p.Ala178Pro) is reported to be deleterious (PMID: 17470695). This indicates that the alanine residue is important for KCNQ1 protein function. In summary, this variant is a rare missense change that has been reported in patients affected with longQT syndrome, and to affected protein function in vitro. In addition, this variant is located in a residue important for protein function. For these reasons, this variant has been classified as Pathogenic.

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