rs199473435

Positions:

chr7-150947854-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BS2_Supporting

The NM_000238.4(KCNH2):c.2717C>T(p.Ser906Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000792 in 1,527,946 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:7O:1

Conservation

PhyloP100: 1.47

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 Uncertain_significance. Variant got 0 ACMG points.

PP5

Variant 7-150947854-G-A is Pathogenic according to our data. Variant chr7-150947854-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67429.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, not_provided=1, Uncertain_significance=4, Pathogenic=1}.

BS2

High AC in GnomAd4 at 6 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/exons	MANE	Protein	UniProt
KCNH2	NM_000238.4 linkuse as main transcript	c.2717C>T	p.Ser906Leu	missense_variant	12/15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.2717C>T	p.Ser906Leu	missense_variant	12/15	1	NM_000238.4	ENSP00000262186	P1	Q12809-1
KCNH2	ENST00000330883.9 linkuse as main transcript	c.1697C>T	p.Ser566Leu	missense_variant	8/11	1		ENSP00000328531		Q12809-2
KCNH2	ENST00000684241.1 linkuse as main transcript	n.3550C>T		non_coding_transcript_exon_variant	10/13

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000722

AC:

AN:

124636

Hom.:

AF XY:

0.0000732

AC XY:

AN XY:

68342

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000427

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000974

Gnomad SAS exome

AF:

0.0000466

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000131

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000836

AC:

115

AN:

1375784

Hom.:

Cov.:

AF XY:

0.0000737

AC XY:

AN XY:

678456

show subpopulations

Gnomad4 AFR exome

AF:

0.0000319

Gnomad4 AMR exome

AF:

0.0000575

Gnomad4 ASJ exome

AF:

0.0000405

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000256

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000958

Gnomad4 OTH exome

AF:

0.0000872

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 906 of the KCNH2 protein (p.Ser906Leu). This variant is present in population databases (rs199473435, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of long QT syndrome. It has been shown to exhibit reduced penetrance (PMID: 19716085, 26743238, 31737537, 36269083; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67429). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 36269083). For these reasons, this variant has been classified as Pathogenic. -

Congenital long QT syndrome

Pathogenic:1Other:1

not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 18, 2024	proposed classification - variant undergoing re-assessment, contact laboratory -

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cardiac arrhythmia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 06, 2023

This missense variant replaces serine with leucine at codon 906 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a reduction in current density in transfected HEK293 cells (PMID: 36269083). This variant has been reported in 15 unrelated individuals affected with long QT syndrome, idiopathic ventricular fibrillation, or suspected of having long QT syndrome (PMID: 19716085, 26743238, 31737537, 31114860, 32893267, 36269083, ClinVar SCV000260666.6). It has been shown that this variant segregates with disease in multiple families of these individuals (PMID: 36269083). One of the probands carried a second known pathogenic variant in the KCNQ1 gene (PMID: 36269083), who had recurrent syncopal events during exercise and emotional stress. This variant has also been reported in an individual suspected of having Brugada syndrome as well as in a stillbirth case (PMID: 30615648, 36269083). This variant has been identified in 9/124636 chromosomes (6/45878 Non-Finnish European chromosomes, 0.0130%) in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. The elevated allele frequency of this variant in the general population suggests this variant may show reduced penetrance. -

Long QT syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 06, 2021

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a VUS-3B . Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Long QT syndrome 2 (MIM#613688). Gain of function is also a known mechanism associated with Short QT syndrome 1 (MIM#609620) (OMIM, PMID: 10753933; PMID: 21777565). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (9 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in-silico predictions and uninformative conservation. (I) 0600 - Variant is located in an annotated domain or motif (C-terminal; PDB) (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant is listed in ClinVar five times as a VUS, has been reported in three LQTS patients (PMID: 19716085, PMID: 26743238, PMID: 31737537), a idiopathic ventricular fibrillation patient (PMID: 31114860) and in a stillbirth case (PMID: 30615648). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 02, 2021

The c.2717C>T (p.S906L) alteration is located in exon 12 (coding exon 12) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 2717, causing the serine (S) at amino acid position 906 to be replaced by a leucine (L). 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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 20, 2022

- -

KCNH2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2024

The KCNH2 c.2717C>T variant is predicted to result in the amino acid substitution p.Ser906Leu. This variant has been reported in multiple individuals with long QT syndrome (Table S2, Kapplinger et al. 2009. PubMed ID: 19716085; Supplemental Table, Marschall et al. 2019. PubMed ID: 31737537), idiopathic ventricular fibrillation (Table 4, Blom et al. 2019. PubMed ID: 31114860), unspecified arrhythmogenic disorders (Table S1, Adler et al. 2016. PubMed ID: 26743238; Table S1, Copier et al. 2023. PubMed ID: 36269083), and one case of stillbirth (Table S2, Sahlin et al. 2019. PubMed ID: 30615648). This variant was also found to co-occur with additional variants in genes associated with arrhythmogenic disorders (CACNA1C, PKP2, RYR2, and AKAP9), including an established pathogenic KCNQ1 p.Thr587Met variant (Table S1, Copier et al. 2023. PubMed ID: 36269083). An in vitro experimental study suggests this variant affects the current density and activation gating of the channel protein (Figure 4, Copier et al. 2023. PubMed ID: 36269083). This variant is reported in 0.013% of alleles in individuals of European (non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/67429/). This variant has been proposed to be associated reduced penetrance with variable clinical presentation (Copier et al. 2023. PubMed ID: 36269083). Although we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

.;T

Eigen

Benign

0.026

Eigen_PC

Benign

0.057

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.88

D;D

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Pathogenic

0.89

MutationAssessor

Benign

0.69

.;N

MutationTaster

Benign

0.65

D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.6

N;N

REVEL

Pathogenic

0.76

Sift

Benign

0.054

T;T

Sift4G

Benign

0.10

T;T

Polyphen

0.99

D;B

Vest4

0.29

MVP

0.99

MPC

0.15

ClinPred

0.060

GERP RS

4.1

Varity_R

0.13

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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