ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.416T>G (p.Leu139Arg) (rs199473460)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000442048 SCV000536354 likely pathogenic not provided 2017-01-20 criteria provided, single submitter clinical testing A variant that is likely pathogenic was identified in the KCNQ1 gene. The L266R variant has not been published in association with LQTS to our knowledge. This variant has been reported in one patient with hypertrophic cardiomyopathy (HCM); however, additional clinical information was not provided (Lopes et al., 2015). Nevertheless, the L266R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; Exome Variant Server). This 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 at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (L266P) has been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), supporting the functional importance of this residue.
Invitae RCV001205787 SCV001377062 likely pathogenic Long QT syndrome 2020-09-23 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 266 of the KCNQ1 protein (p.Leu266Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with long QT syndrome (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 393006). 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 and their clinical significance is uncertain. This variant disrupts the p.Leu266 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22949429, 17470695, 17905336, 21451124, 1467812, 21118729). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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