NM_000238.4:c.1468G>A

Variant names:

• chr7-150952514-C-T
• rs28928905
• NM_000238.4:c.1468G>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.1468G>A​(p.Ala490Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.75

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 topological_domain Cytoplasmic (size 23) in uniprot entity KCNH2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 7-150952514-C-T is Pathogenic according to our data. Variant chr7-150952514-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150952514-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1468G>A	p.Ala490Thr	missense_variant	Exon 6 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10	c.1468G>A	p.Ala490Thr	missense_variant	Exon 6 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461826 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:3

Aug 01, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1468G>A (p.Ala490Thr) variant of the KCNH2 gene has been identified in at least five individuals with Long QT syndrome (LQTS) (PMID: 11170080, 18441445, 35470680, 22581653, 35492841) and in an individual with severe bradycardia (PMID: 20975234). This variant co-segregated with a prolonged or borderline QT interval in a family with seven affected individuals from three generations (PMID: 18808722). This variant was also identified in an individual referred for LQTS genetic testing (PMID: 19716085). Electrophysiology studies showed that this variant caused voltage gate dysfunction and reduced current density of the mutant potassium channel (PMID: 11170080, 20975234). In vivo cardiac assay using zebra fish embryo showed that this variant is unable to rescue repolarization (PMID: 23303164). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.972). This variant is found to be absent in the general population database (gnomAD). This variant is reported in ClinVar (ClinVar ID:14430). Therefore, the c.1468G>A (p.Ala490Thr) variant in the KCNH2 gene is classified as likely pathogenic. -

Nov 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 490 of the KCNH2 protein (p.Ala490Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 18808722, 20975234). ClinVar contains an entry for this variant (Variation ID: 14430). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 11170080, 20975234, 23303164). For these reasons, this variant has been classified as Pathogenic. -

Mar 24, 2023

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1468G>A (p.Ala490Thr) variant of the KCNH2 gene has been identified in at least five individuals with Long QT syndrome (LQTS) (PMID: 11170080, 18441445, 35470680, 22581653, 35492841) and in an individual with severe bradycardia (PMID: 20975234). This variant co-segregated with a prolonged or borderline QT interval in a family with seven affected individuals from three generations (PMID: 18808722). This variant was also identified in an individual referred for LQTS genetic testing (PMID: 19716085). Electrophysiology studies showed that this variant caused voltage gate dysfunction and reduced current density of the mutant potassium channel (PMID: 11170080, 20975234). In vivo cardiac assay using zebra fish embryo showed that this variant is unable to rescue repolarization (PMID: 23303164). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.972). This variant is found to be absent in the general population database (gnomAD). This variant is reported in ClinVar (ClinVar ID:14430). Therefore, the c.1468G>A (p.Ala490Thr) variant in the KCNH2 gene is classified as likely pathogenic. -

Long QT syndrome 2 Pathogenic:1

Mar 07, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1468G>A (p.Ala490Thr) variant in the KCNH2 has been identified in at least four unrelated individuals with long QT syndrome (LQTS) (PMIDs: 11170080, 18441445, 18808722, 19716085) and has been found to co-segregate with LQTS (PMID 18808722). This variant was observed de novo in a proband with LQTS (PMID 11170080). This variant is absent from public databases, occurs at a position where a different change(p.A490P) have been shown to segregate with LQTS in a large family with 100% penetrance, located in a functional domain where pathogenic variants have been identified and predicted to be damaging by multiple algorithms. Additionally two independent functional studies implicate this variant to result in loss of channel function (PMIDs 11170080 and 20975234). Therefore, this variant is classified as a pathogenic variant in accordance with ACMG guidelines. -

Long QT syndrome, bradycardia-induced Pathogenic:1

Feb 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Sep 12, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Previously reported in association with LQTS (PMID: 11170080, 18441445, 18808722, 19716085); Published functional studies demonstrated that A490T resulted in significantly reduced whole cell currents compared to the wild-type (PMID: 20975234); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19716085, 18441445, 11170080, 23303164, 31447099, 36861347, 35492841, 20975234, 18808722) -

Cardiovascular phenotype Pathogenic:1

Apr 23, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A490T variant (also known as c.1468G>A), located in coding exon 6 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1468. The alanine at codon 490 is replaced by threonine, an amino acid with similar properties. This alteration has been detected in several individuals with prolonged QT as well as in a long QT syndrome (LQTS) cohort (Yoshida H et al. Am. J. Med. Genet., 2001 Feb;98:348-52; Zhang X et al. BMC Med. Genet., 2008 Sep;9:87; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). In one family, this variant has been reported to segregate with disease (Zhang X et al. BMC Med. Genet., 2008 Sep;9:87). Functional studies indicate that this alteration disrupts normal protein function (Yoshida H et al. Am. J. Med. Genet., 2001 Feb;98:348-52; Oka Y et al. Circ. J., 2010 Nov;74:2562-71; Jou CJ et al. Circ. Res., 2013 Mar;112:826-30). 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

-

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

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:11170080;PMID:18441445;PMID:18808722;PMID:19716085;PMID:20975234). 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	0.65
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.6	D;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0090	D;D;.
Sift4G	Uncertain	0.012	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.98
MutPred		0.88		.;Gain of methylation at K495 (P = 0.132);.;
MVP		0.99
MPC		2.2
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75
gMVP		0.95

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: rs28928905; hg19: chr7-150649602;