7-150947708-G-C

Variant names:

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: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

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]

KCNH2 links:

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
KCNH2	NM_000238.4 link	c.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	UniProt
KCNH2	ENST00000262186.10 link	c.2863C>G	p.Leu955Val	missense_variant	Exon 12 of 15	1	NM_000238.4	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000330883.9 link	c.1843C>G	p.Leu615Val	missense_variant	Exon 8 of 11	1		ENSP00000328531.4	Q12809-2
KCNH2	ENST00000684241.1 link	n.3696C>G		non_coding_transcript_exon_variant	Exon 10 of 13

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152178

Hom.:

Cov.:

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:

AN:

194206

Hom.:

AF XY:

0.0000281

AC XY:

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:

AN:

1433222

Hom.:

Cov.:

AF XY:

0.0000535

AC XY:

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:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

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.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000338

AC:

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

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 -

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) -

Jan 18, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 -

Long QT syndrome

Pathogenic:1Uncertain:2Other:1

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. -

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

- -

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. -

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. -

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

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

.;T

Eigen

Benign

0.054

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.82

T;T

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.30

T;T

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

0.90

.;L

PrimateAI

Uncertain

0.63

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over