Submissions for variant NM_172057.2(KCNH2):c.1880C>T (p.Pro627Leu) (rs199473016)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000252864	SCV000320494	likely benign	Cardiovascular phenotype	2016-10-27	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),In silico models in agreement (benign)
Invitae	RCV000707524	SCV000836625	uncertain significance	Long QT syndrome	2018-03-26	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 967 of the KCNH2 protein (p.Pro967Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs199473016, ExAC 0.2%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with sudden infant death syndrome as well as in a healthy control (PMID: 14975928). ClinVar contains an entry for this variant (Variation ID: 67451). Experimental studies have shown that this missense change is electrophysiologically indistinguishable from the wild type channel (PMID:14975928). 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	RCV000058178	SCV000089698	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:14661677;PMID:19841300).