ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.730G>C (p.Ala244Pro) (rs199473412)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230409 SCV000283872 likely pathogenic Long QT syndrome 2019-09-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 371 of the KCNQ1 protein (p.Ala371Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with longQT syndrome in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 237221). 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.Ala371 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16556865, 9386136, 10973849, 20196769). 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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