chr7-150952720-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

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

Scores

15
3
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2O:1

Conservation

PhyloP100: 9.81
Variant links:
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]

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ACMG classification

Classification made for transcript

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: {Uncertain_significance=2, Likely_pathogenic=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
KCNH2NM_000238.4 linkc.1262C>T p.Thr421Met missense_variant Exon 6 of 15 ENST00000262186.10 NP_000229.1 Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNH2ENST00000262186.10 linkc.1262C>T p.Thr421Met missense_variant Exon 6 of 15 1 NM_000238.4 ENSP00000262186.5 Q12809-1

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
show subpopulations
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:2Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Long QT syndrome Pathogenic:1Uncertain: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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199472894; hg19: chr7-150649808; API