ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.2345C>T (p.Pro782Leu) (rs531460655)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181917 SCV000234220 uncertain significance not specified 2017-01-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNH2 gene. The P1122L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,400 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 P1122L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, to our knowledge no studies have been performed to determine the functional effect of the P1122L variant.
Invitae RCV000525474 SCV000627485 uncertain significance Long QT syndrome 2017-07-20 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1122 of the KCNH2 protein (p.Pro1122Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs531460655, ExAC 0.06%). This variant has not been reported in the literature in individuals with KCNH2-related disease. ClinVar contains an entry for this variant (Variation ID: 200534). 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 tolerated, 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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