rs199472906

Positions:

• chr7-150952561-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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: Genomes: not found (cov: 32)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 9.80

Genes affected

KCNH2 (HGNC:6251): (potassium voltage-gated channel subfamily H member 2) This gene encodes a component of a voltage-activated potassium channel found in cardiac muscle, nerve cells, and microglia. Four copies of this protein interact with one copy of the KCNE2 protein to form a functional potassium channel. Mutations in this gene can cause long QT syndrome type 2 (LQT2). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 7-150952561-G-A is Pathogenic according to our data. Variant chr7-150952561-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150952561-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNH2	NM_000238.4	c.1421C>T	p.Thr474Ile	missense_variant	6/15	ENST00000262186.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNH2	ENST00000262186.10	c.1421C>T	p.Thr474Ile	missense_variant	6/15	1	NM_000238.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 10, 2014

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2024

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

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	.;D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.6	D;D;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.012	D;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.99
MutPred		0.87		.;Loss of glycosylation at T474 (P = 0.017);.;
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.84
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199472906; hg19: chr7-150649649;