ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.343G>T (p.Asp115Tyr) (rs199472712)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182104 SCV000234407 likely pathogenic not provided 2017-05-15 criteria provided, single submitter clinical testing The D242Y variant has been reported in association with LQTS in one individual (Jons et al., 2009). The D242Y 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. The D242Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs in the S4 voltage sensor at a position that is class-conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in this same residue (D242N) and in nearby residues (L239P, V241F, V241G, R243C, R243S, R243P) have been reported in the Human Gene Mutation Database in association with arrhythmia (Stenson et al., 2014), supporting the functional importance of this region of the protein.Therefore, this variant is likely pathogenic.
Invitae RCV000476524 SCV000543318 likely pathogenic Long QT syndrome 2018-08-03 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 242 of the KCNQ1 protein (p.Asp242Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with long QT syndrome (LQTS) (PMID: 19490272). ClinVar contains an entry for this variant (Variation ID: 67099). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Asp242Asn) is reported to be deleterious (PMID: 9799083, 19490272, 25705178). This indicates that the p.Asp242 residue is important for KCNQ1 protein function. In summary, this variant has not been observed in control individuals, has been reported in an individual affected with LQTS and alters a residue important for protein function. In the absence of functional data or conclusive segregation data, at this time this variant has been classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057739 SCV000089258 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:19490272). 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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