NM_000238.4:c.1421C>T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000238.4(KCNH2):c.1421C>T(p.Thr474Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.1421C>T | p.Thr474Ile | missense_variant | Exon 6 of 15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
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). -
Cardiovascular phenotype Pathogenic:1
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. -
Congenital long QT syndrome Other:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at