ClinVar Miner

Submissions for variant NM_000218.2(KCNQ1):c.377A>T (p.His126Leu) (rs794728579)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182329 SCV000234632 likely pathogenic not provided 2011-08-25 criteria provided, single submitter clinical testing This missense change is denoted His126Leu (aka H126L) at the protein level and c.377 A>T at the cDNA level. The His126Leu variant in the KCNQ1 gene has not been reported previously as a disease-causing mutation nor as a benign polymorphism, to our knowledge. His126Leu results in a non-conservative amino acid substitution of a positively charged Histidine with a non-polar Leucine at a residue that is conserved across species. As a result, in silico analysis predicts His126Leu is probably damaging to the protein structure/function (Adzhubei IA et al., 2010, Schwarz JM et al., 2011). In addition, mutations in nearby codons (Cys122Tyr, Phe127Leu) have been reported in association with LQTS, supporting the functional importance of this region of the protein. Furthermore, the His126Leu variant was not detected in 470 alleles from control individuals of various ethnic backgrounds tested at GeneDx, indicating it is not a common benign variant. In summary, while the His126Leu variant is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant with the clinical and molecular information available at this time. The variant is found in LQT panel(s).
Invitae RCV000631593 SCV000752675 uncertain significance Long QT syndrome 2017-10-06 criteria provided, single submitter clinical testing This sequence change replaces histidine with leucine at codon 126 of the KCNQ1 protein (p.His126Leu). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNQ1-related disease. ClinVar contains an entry for this variant (Variation ID: 200911). This variant identified in the KCNQ1 gene is located in the transmembrane S1 region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNQ1-topology. It is unclear how this variant impacts the function of this protein. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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