ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.2078T>C (p.Leu693Pro) (rs199472983)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181836 SCV000234139 uncertain significance not provided 2016-11-30 criteria provided, single submitter clinical testing The L693P substitution in the KCNH2 gene has been reported in one patient with LQTS, and it was absent from 2,600 control alleles (Kapplinger J et al., 2009). Also, L693P 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. L693P results in a semi-conservative amino acid substitution resulting in the gain of a sterically-constrained Proline residue at a position that is conserved across species. Variants in nearby residues (H687Y, R694H, R696C) have been reported in association with LQTS, further supporting the functional importance of this region of the protein. Also, in silico analysis predicts L693P is damaging to the protein structure/function. Given the available evidence, we interpret L693P as a variant of uncertain significance.
Invitae RCV000546253 SCV000627449 likely pathogenic Long QT syndrome 2017-10-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 693 of the KCNH2 protein (p.Leu693Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with long QT syndrome (PMID: 22949429) and was shown to segregate with long QT syndrome in an extended family (Invitae). This variant has also been observed in an individual referred for long QT syndrome genetic testing (PMID: 19716085), though it is possible that this is the same individual as referenced in PMID: 22949429. ClinVar contains an entry for this variant (Variation ID: 67359). This variant identified in the KCNH2 gene is located in the cytoplasmic C-terminal region of the resulting protein (PMID: 19841300, 25348405). For more information about the location of this variant, please visit www.invitae.com/KCNH2-topology. 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 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.
Ambry Genetics RCV000624294 SCV000742444 uncertain significance Inborn genetic diseases 2017-05-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058079 SCV000089599 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:19716085;PMID:19841300). 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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