rs199473435

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP2PP5BS2_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). Synonymous variant affecting the same amino acid position (i.e. S906S) has been classified as Likely benign.

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:7U:7O:1

Conservation

PhyloP100: 1.47

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

long QT syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
long QT syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
short QT syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
short QT syndrome type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: MODERATE, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp

KCNH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 158 curated pathogenic missense variants (we use a threshold of 10). The gene has 38 curated benign missense variants. Gene score misZ: 3.3724 (above the threshold of 3.09). Trascript score misZ: 2.4846 (below the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome 2, Brugada syndrome, short QT syndrome type 1, short QT syndrome, long QT syndrome.

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 VariationId is 67429.

BS2

High AC in GnomAd4 at 6 AD 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.2717C>T	p.Ser906Leu	missense_variant	Exon 12 of 15	ENST00000262186.10	NP_000229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 link	c.2717C>T	p.Ser906Leu	missense_variant	Exon 12 of 15	1	NM_000238.4	ENSP00000262186.5

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

GnomAD2 exomes

AF:

0.0000722

AC:

AN:

124636

AF XY:

0.0000732

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 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

African (AFR)

AF:

0.0000319

AC:

AN:

31308

American (AMR)

AF:

0.0000575

AC:

AN:

34764

Ashkenazi Jewish (ASJ)

AF:

0.0000405

AC:

AN:

24686

East Asian (EAS)

AF:

0.00

AC:

AN:

35582

South Asian (SAS)

AF:

0.0000256

AC:

AN:

78146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34530

Middle Eastern (MID)

AF:

0.000247

AC:

AN:

4048

European-Non Finnish (NFE)

AF:

0.0000958

AC:

103

AN:

1075354

Other (OTH)

AF:

0.0000872

AC:

AN:

57366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome

Pathogenic:3

Sep 26, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; internal data). 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. -

Oct 28, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: KCNH2 c.2717C>T (p.Ser906Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 124636 control chromosomes. c.2717C>T has been reported in the literature in the heterozygous state multiple individuals affected with Long QT Syndrome and segregated with disease in multiple families and showed reduced penetrance (Kapplinger_2009, Coopier_2023). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Copier_2023). The following publications have been ascertained in the context of this evaluation (PMID: 36269083, 19716085). ClinVar contains an entry for this variant (Variation ID: 67429). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1Uncertain:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KCNH2: PP1:Strong, PM2, PS4:Moderate, PS3:Supporting -

Cardiovascular phenotype

Pathogenic:1Uncertain:1

Apr 02, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Oct 03, 2024

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4_mod; PP1_mod; PS3_supp; PP2 -

Congenital long QT syndrome

Pathogenic:1Other:1

Mar 18, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

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:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Short QT syndrome type 1;C3150943:Long QT syndrome 2

Uncertain:2

Jan 06, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiac arrhythmia

Pathogenic:1

Nov 14, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. 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). 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

Oct 11, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 (v4) <0.001 for a dominant condition (121 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 has been reported as either a VUS or likely pathogenic in individuals with LQTS, idiopathic ventricular fibrillation, and in a stillbirth case (ClinVar, PMIDs: 36269083, 32893267, 19716085, 26743238, 31737537, 31114860, 30615648). (I) 0906 - Segregation evidence for this variant is inconclusive. This variant segregated with features of LQTS in seven individuals from multiple families. However, five gene positive individuals were unaffected at the time of assessment (PMID: 36269083). (I) 1004 - This variant has moderate functional evidence supporting normal protein function. Automated patch clamp functional studies have shown that this variant results in a 36% reduction in current density, which is comparable to some benign variants. Additionally, this variant has normal channel gating deactivation (personal communication with Victor Chang Victor Chang Cardiac Research Institute, PMID: 36269083). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

KCNH2-related disorder

Uncertain:1

May 24, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

CardioboostArm

Uncertain

0.85

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.37

CADD

Benign

(source)

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

PhyloP100

1.5

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

Mutation Taster

=8/92

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over