Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000182021 | SCV000234324 | pathogenic | not provided | 2014-10-10 | criteria provided, single submitter | clinical testing | The Thr474Ile mutation in the KCNH2 gene has been published previously in association with LQTS. Tanaka et al. (1997) reported the Thr474Ile mutation co-segregating with LQTS in a Japanese family, and did not detect the mutation in 80 normal individuals.Thr474Ile, which occurs in the S2-S3 region of KCNH2, represents a non-conservative amino acid replacement of a polar Threonine residue with a non-polar Isoleucine residue at a position in the protein that is highly conserved across species throughout evolution. Mutations affecting nearby codons (Asn470Asp, Thr473Asn, Tyr475Cys, Val476Ile) have been reported in association with LQTS, further supporting the functional importance of this region of the protein. Furthermore, Thr474Ile was not detected in up to 600 control chromosomes of African American and Caucasian ethnic groups tested at GeneDx, indicating it is not a common benign polymorphism in these populations. The variant is found in LQT panel(s). |
| Ambry Genetics | RCV002390207 | SCV002699783 | likely pathogenic | Cardiovascular phenotype | 2024-03-18 | criteria provided, single submitter | clinical testing | The p.T474I variant (also known as c.1421C>T), located in coding exon 6 of the KCNH2 gene, results from a C to T substitution at nucleotide position 1421. The threonine at codon 474 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in probands with long QT syndrome, though clinical information was often limited (Tanaka T et al. Circulation. 1997 Feb;95:565-7; Lieve KV et al. Genet Test Mol Biomarkers. 2013;17:553-61; Ishibashi K et al. Heart. 2017;103:1374-1379). This variant was reported to segregate with disease in one Japanese family; however, the segregation data were not provided (Tanaka T et al. Circulation. 1997 Feb;95:565-7). Functional studies suggest that this alteration causes a trafficking defect and results in reduced KCNH2 function (Nakajima T et al. Circ. Res. 1998;83:415-22; Anderson CL et al. Circulation. 2006;113:365-73; Jou CJ et al. Circ. Res. 2013;112:826-30; Zhang Y et al. Front Pharmacol. 2022 Oct;13:1010119). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Cardiovascular Biomedical Research Unit, |
RCV000057906 | SCV000089426 | 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:9024139;PMID:16432067;PMID:9694858). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. |