ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1001C>T (p.Pro334Leu) (rs199472888)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181776 SCV000234079 pathogenic not provided 2014-07-15 criteria provided, single submitter clinical testing p.Pro334Leu (CCC>CTC): c.1001 C>T in exon 5 of the KCNH2 gene (NM_000238.2). The P334L variant in the KCNH2 gene has been reported in association with LQTS (Lupoglazoff et al., 2001; Imboden et al., 2006). The P334L was identified as a novel mutation in 1 out of 57 affected individual with LQTS, and was absent from 150 control chromosomes (Lupoglazoff et al., 2001). Additionally, of the 240 families of European ancestry with LQTS studied by Imoboden et al., 2006, one family was reported to harbor the P334L mutation. The P334L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (R328C, D342V) have been reported in association with LQTS, supporting the functional importance of this region of the protein. Furthermore, the P334L variant 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. In summary, P334L in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Invitae RCV001055822 SCV001220232 uncertain significance Long QT syndrome 2019-02-01 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 334 of the KCNH2 protein (p.Pro334Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with long QT syndrome (PMID: 11222472, 17088455, Invitae). ClinVar contains an entry for this variant (Variation ID: 67161). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057868 SCV000089388 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:11222472). 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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