chr7-150952720-G-A

Variant names:

• chr7-150952720-G-A
• rs199472894
• NM_000238.4:c.1262C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000238.4(KCNH2):​c.1262C>T​(p.Thr421Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KCNH2 NM_000238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 O:1
• Conservation: PhyloP100: 9.81

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a transmembrane_region Helical; Name=Segment S1 (size 20) in uniprot entity KCNH2_HUMAN there are 6 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, 0.957
• PP5: Variant 7-150952720-G-A is Pathogenic according to our data. Variant chr7-150952720-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67173.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2, not_provided=1}. Variant chr7-150952720-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4	c.1262C>T	p.Thr421Met	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.1262C>T	p.Thr421Met	missense_variant	Exon 6 of 15	1	NM_000238.4	ENSP00000262186.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461886 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Pathogenic:1 Uncertain:1

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 23136156, 23303164). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 67173). This missense change has been observed in individual(s) with long QT syndrome (PMID: 15840476, 19716085, 23136156). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 421 of the KCNH2 protein (p.Thr421Met). -

Sep 06, 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.1262C>T (p.Thr421Met) variant is located on the exon 6 of KCNH2 gene, that encodes for potassium voltage-gated channel subfamily H member 2. This variant has been identified in at least four unrelated individuals affected with long QT syndrome (LQTS) (PMID: 19716085, 23136156, 32893267, 29884292) and in one individual referred for LQTS genetic testing (PMID: 15840476). In-vitro rat myocyte studies demonstrated that when co-expressed with wildtype, this variant causes a dominant negative effect by reducing the potassium current due to abnormal protein trafficking and altered channel gating (PMID: 23136156). In-vivo functional studies using kcnh2-knockdown embryonic zebrafish revealed reduced (5.8%) restoration of normal repolarization (PMID: 23303164). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.95). This variant lies in the transmembrane domain of the protein (404-659 amino acid residues) and missense variants in this region are statistically more likely to be associated with LQTS (PMID: 32893267) phenotype. This variant is absent in the general population database, gnomAD. Therefore, the c.1262C>T (p.Thr421Met) variant in the KCNH2 gene is classified as likely pathogenic. -

not provided Pathogenic:1

Dec 26, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: decreased ability to restore normal repolarization in KCNH2-knockdown embryonic zebrafish in vivo and reduced potassium current due to abnormal protein trafficking and altered channel gating in vitro (PMID: 23303164, 23136156); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23136156, 19716085, 15840476, 16432067, 22581653, 28476926, 33449212, 35210539, 23303164, 34709746, 30219255) -

not specified Uncertain:1

Sep 23, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNH2 c.1262C>T (p.Thr421Met) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1262C>T has been reported in the literature in an individual affected with long QT syndrome with a sudden near death episode with family history of sudden death (e.g. Balijepali_2012) and in additional individuals affected with Long QT Syndrome without strong evidence for causality (e.g. Tester_2005, Shimizu_2010, Kozek_2021, Kapplinger_2009). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a partially trafficking-deficient channel protein with altered channel gating and kinetics of activation and deactivation (e.g. Balijepali_2012). ClinVar contains an entry for this variant (Variation ID: 67173). Based on the evidence outlined above, the variant was classified as VUS-possibly 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:15840476;PMID:16432067;PMID:19716085). 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	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	.;D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	.;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.7	D;D;N
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.88
MutPred		0.82		.;Gain of helix (P = 0.0325);.;
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.85
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199472894; hg19: chr7-150649808;