7-150974931-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000238.4(KCNH2):​c.87C>A​(p.Phe29Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,354 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

11
5
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 3.28
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.974
PP5
Variant 7-150974931-G-T is Pathogenic according to our data. Variant chr7-150974931-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 67538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150974931-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNH2NM_000238.4 linkc.87C>A p.Phe29Leu missense_variant Exon 2 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.87C>A p.Phe29Leu missense_variant Exon 2 of 15 1 NM_000238.4 ENSP00000262186.5 Q12809-1
KCNH2ENST00000532957.5 linkn.310C>A non_coding_transcript_exon_variant Exon 2 of 9 2

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
6.89e-7
AC:
1
AN:
1452354
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
722062
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:
0.0000205
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Long QT syndrome Pathogenic:2
May 31, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces phenylalanine with leucine at codon 29 of the KCNH2 protein (p.Phe29Leu). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect KCNH2 protein function (PMID: 26403377, 22396785, 25417810, 21536673, 23721480, 10187793, 30988392). This variant has been observed in several individuals with long QT syndrome (LQTS) and observed to segregate with LQTS in a family (PMID: 17088455, 26403377). ClinVar contains an entry for this variant (Variation ID: 67538). -

Jan 10, 2024
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.87C>A (p.Phe29Leu) variant in KCNH2 gene, that encodes for potassium voltage-gated channel subfamily H member 2, has been identified in multiple unrelated probands (>10) with Long QT syndrome (PMID: 26403377, 29343803, 28235848, 32893267). This variant has been identified as a founder variant in thirty-three members of five apparently unrelated Danish families with congenital long QT syndrome (PMID:26403377). This variant has also been reported in one individual with sudden cardiac death (PMID: 31729605). Several functional studies using transfected HEK cells and Xenopus laevis oocytes revealed a loss-of-function phenotype with trafficking defects, accelerated deactivation of functional channels, altered channel gating, reduced steady-state inactivation current density and a positive voltage shift in inactivation, compared to wild type (PMID: 26403377, 10187793, 21536673, 31557540, 30988392, 22396785). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.843). This variant is absent in the general population database, gnomAD and interpreted as pathogenic in ClinVar (ClinVar ID: 67538). Therefore, the c.87C>A (p.Phe29Leu) variant in the KCNH2 gene is classified as 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:10187793;PMID:10973849;PMID:11668638;PMID:11854117;PMID:15840476;PMID:15851171;PMID:16937190;PMID:19716085;PMID:21536673;PMID:22396785). 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
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.85
D
Eigen
Benign
0.027
Eigen_PC
Benign
0.045
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.97
D
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.0
M
PrimateAI
Pathogenic
0.94
D
PROVEAN
Uncertain
-3.5
D
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0050
D
Polyphen
0.0
B
Vest4
0.96
MutPred
0.82
Loss of methylation at K28 (P = 0.035);
MVP
1.0
MPC
1.2
ClinPred
0.97
D
GERP RS
2.1
Varity_R
0.85
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

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

Other links and lift over

dbSNP: rs199472830; hg19: chr7-150672019; API