7-150947708-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS2_Supporting

The NM_000238.4(KCNH2):​c.2863C>G​(p.Leu955Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000058 in 1,585,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000053 ( 0 hom., cov: 33)
Exomes š‘“: 0.000059 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

4
4
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:9O:2

Conservation

PhyloP100: 1.12
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 Likely_benign. Variant got -1 ACMG points.

PP5
Variant 7-150947708-G-C is Pathogenic according to our data. Variant chr7-150947708-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67445.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=8, not_provided=2}.
BP4
Computational evidence support a benign effect (MetaRNN=0.29663557). . Strength limited to SUPPORTING due to the PP5.
BS2
High AC in GnomAd4 at 8 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNH2NM_000238.4 linkc.2863C>G p.Leu955Val missense_variant Exon 12 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.2863C>G p.Leu955Val missense_variant Exon 12 of 15 1 NM_000238.4 ENSP00000262186.5 Q12809-1
KCNH2ENST00000330883.9 linkc.1843C>G p.Leu615Val missense_variant Exon 8 of 11 1 ENSP00000328531.4 Q12809-2
KCNH2ENST00000684241.1 linkn.3696C>G non_coding_transcript_exon_variant Exon 10 of 13

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000257
AC:
5
AN:
194206
Hom.:
0
AF XY:
0.0000281
AC XY:
3
AN XY:
106716
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000598
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000586
AC:
84
AN:
1433222
Hom.:
0
Cov.:
36
AF XY:
0.0000535
AC XY:
38
AN XY:
710940
show subpopulations
Gnomad4 AFR exome
AF:
0.0000303
Gnomad4 AMR exome
AF:
0.0000733
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:
0.0000655
Gnomad4 OTH exome
AF:
0.000135
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152296
Hom.:
0
Cov.:
33
AF XY:
0.0000537
AC XY:
4
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000902
Hom.:
0
Bravo
AF:
0.000121
ExAC
AF:
0.0000338
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:9Other:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:2Uncertain:3
Feb 22, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BS4, PP2, PM2, PS3_supporting, PS4_moderate -

Jun 03, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Functional studies conducted using CHO and HEK cells demonstrated that the L955V variant led to a defect of protein trafficking, resulting in greatly reduced ion current in the plasma membrane (Biliczki et al., 2008); nevertheless, it is unclear how these studies may translate to a pathogenic role in vivo; This variant is associated with the following publications: (PMID: 18675227, 22581653, 11524404, 33258288, 10973849) -

Nov 06, 2017
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

KCNH2: PS4:Moderate, PM2:Supporting, PS3:Supporting -

Jan 18, 2022
AiLife Diagnostics, AiLife Diagnostics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Long QT syndrome Pathogenic:1Uncertain:2Other:1
Mar 21, 2017
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 13, 2024
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces leucine with valine at codon 955 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant impairs cellular trafficking of the protein and results in reduced potassium channel currents (PMID: 18675227). This variant has been reported in two individuals affected with long QT syndrome (PMID: 18675227, Pacheco et al., 2013) and in an individual affected with sudden unexplained death with a history of syncope (Buscemi et al., 2015). This variant has been identified in 5/194206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

-
GenomeConnect, ClinGen
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Oct 15, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 955 of the KCNH2 protein (p.Leu955Val). This variant is present in population databases (rs199473012, gnomAD 0.005%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 18675227). ClinVar contains an entry for this variant (Variation ID: 67445). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 18675227). 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. -

not specified Uncertain:1
Jul 22, 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.2863C>G (p.Leu955Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 194206 control chromosomes, predominantly at a frequency of 6e-05 within the Non-Finnish European subpopulation in the gnomAD database. c.2863C>G has been reported in the literature in individuals affected with Recurrent Syncope, Neurodevelopmental disorders and sudden unexpected death with Peripartum cardiomyopathy by postmortem (Biliczki_2008, Quaio_2020, Grondin_2022, Siskind_2022). 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 about 25% of normal Potassium current, less than 10% of WT proteins from a heterologous expression in human embryonic kidney cells (Biliczki_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18675227, 35352813, 33258288, 36203036). ClinVar contains an entry for this variant (Variation ID: 67445). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Cardiovascular phenotype Uncertain:1
Dec 06, 2019
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2863C>G (p.L955V) alteration is located in exon 12 (coding exon 12) of the KCNH2 gene. This alteration results from a C to G substitution at nucleotide position 2863, causing the leucine (L) at amino acid position 955 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Short QT syndrome type 1;C3150943:Long QT syndrome 2 Uncertain:1
Jun 24, 2022
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

Cardiac arrhythmia Uncertain:1
May 06, 2024
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces leucine with valine at codon 955 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. A functional study has shown that this variant impairs cellular trafficking of the protein and results in reduced potassium channel currents (PMID: 18675227). This variant has been reported in two individuals affected with long QT syndrome (PMID: 18675227, Pacheco et al., 2013) and in an individual affected with sudden unexplained death with a history of syncope (Buscemi et al., 2015). This variant has been identified in 5/194206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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:18675227). 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
Benign
0.084
BayesDel_addAF
Pathogenic
0.16
D
BayesDel_noAF
Pathogenic
0.14
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.38
.;T
Eigen
Benign
0.054
Eigen_PC
Benign
0.16
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.82
T;T
M_CAP
Pathogenic
0.53
D
MetaRNN
Benign
0.30
T;T
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Benign
0.90
.;L
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-0.97
N;N
REVEL
Uncertain
0.60
Sift
Benign
0.24
T;T
Sift4G
Benign
0.16
T;T
Polyphen
0.51
P;P
Vest4
0.27
MVP
0.96
MPC
0.63
ClinPred
0.40
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
3.2
Varity_R
0.21
gMVP
0.59

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: rs199473012; hg19: chr7-150644796; API