7-150952514-C-T

Variant names:

• chr7-150952514-C-T
• rs28928905
• NM_000238.4:c.1468G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 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. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A490V) has been classified 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:8 O:1
• Conservation: PhyloP100: 7.75
• Publications: 19 publications found

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]

KCNH2 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• short QT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• short QT syndrome type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000238.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-150952513-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 862292.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 14430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000238.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	NM_000238.4	MANE Select	c.1468G>A	p.Ala490Thr	missense	Exon 6 of 15	NP_000229.1
	KCNH2	NM_001406753.1		c.1180G>A	p.Ala394Thr	missense	Exon 4 of 13	NP_001393682.1
	KCNH2	NM_172056.3		c.1468G>A	p.Ala490Thr	missense	Exon 6 of 9	NP_742053.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH2	ENST00000262186.10	TSL:1 MANE Select	c.1468G>A	p.Ala490Thr	missense	Exon 6 of 15	ENSP00000262186.5
	KCNH2	ENST00000330883.9	TSL:1	c.448G>A	p.Ala150Thr	missense	Exon 2 of 11	ENSP00000328531.4
	KCNH2	ENST00000461280.2	TSL:1	n.766G>A		non_coding_transcript_exon	Exon 2 of 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:3

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.

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.

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.

Cardiac arrhythmia Pathogenic:1

Nov 13, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with threonine at codon 490 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. This variant is located within the conserved transmembrane domain of the KCNH2 protein. Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Multiple functional studies have shown that this variant results in a partial loss of potassium channel function (PMID: 11170080, 20975234, 23303164). This variant has been reported in seven unrelated individuals affected with long QT syndrome (PMID: 11170080, 18441445, 18808722, 19716085, 22581653, 35470680, 35492841, 36861347). In one of these probands, this variant was reported to be de novo (PMID: 11170080). This variant has shown segregation with a prolonged or borderline QT interval in seven individuals in a family across three generations (PMID 18808722). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.012	D
Polyphen		0.99	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
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28928905; hg19: chr7-150649602;