ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.179T>C (p.Leu60Pro) (rs199473399)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046081 SCV000074094 likely pathogenic Long QT syndrome 2020-09-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 187 of the KCNQ1 protein (p.Leu187Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs199473399, ExAC 0.002%). This variant has been reported to segregate with LQT (LQT) syndrome in a large multigenerational family (PMID: 18808722). It has also been reported in several individuals affected with LQT syndrome (PMID: 18808722, 23631430). However, in one individual, one pathogenic allele c.1663C>T (p.Arg555Cys) was also identified in the KCNQ1 gene. The phase of these two variants is unknown. ClinVar contains an entry for this variant (Variation ID: 53066). This variant has been reported to have conflicting or insufficient data to determine the effect on KCNQ1 protein function (PMID: 30571187). 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.
GeneDx RCV000182084 SCV000234387 pathogenic not provided 2014-05-13 criteria provided, single submitter clinical testing p.Leu187Pro (CTC>CCC): c.560 T>C in exon 3 of the KCNQ1 gene (NM_000218.2). The L187P mutation in the KCNQ1 gene has been reported previously in association with LQTS (Zhang X et al., 2008). The L187P mutation was found to co-segregate with the LQTS phenotype in the 7 generations a large family with LQTS, and this mutation was absent in 200 control individuals (Zhang X et al., 2008). In addition, the L187P mutation 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. Located in the linker between the S2 and S3 domains, the L187 residue is not uniformly conserved across species, however variation is limited to similar non-polar amino acids. The L187P mutation results in 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. Furthermore, mutations in nearby codons (G186R, G186S, G189R, G189E) have also been reported in association with LQTS, further supporting the functional importance of this region of the protein. In summary, L187P in the KCNQ1 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057701 SCV000089220 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:18808722). 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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