Submissions for variant NM_172057.2(KCNH2):c.1697C>T (p.Ser566Leu) (rs199473435)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000203863	SCV000260666	uncertain significance	Long QT syndrome	2018-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces serine with leucine at codon 906 of the KCNH2 protein (p.Ser906Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. While this variant is not present in population databases (rs199473435), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in several individuals referred for long QT syndrome testing (PMID: 19716085, 26743238). ClinVar contains an entry for this variant (Variation ID: 67429). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000455329	SCV000539442	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 2 probands.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute	RCV000203863	SCV000748010	uncertain significance	Long QT syndrome	2017-02-06	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000765943	SCV000897364	uncertain significance	Short QT syndrome 1; Long QT syndrome 2	2018-10-31	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust	RCV000058154	SCV000089674	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). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.