chr7-150952523-C-T

Position:

chr7-150952523-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS2_Supporting

The NM_000238.4(KCNH2):c.1459G>A(p.Gly487Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000502 in 1,614,120 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

KCNH2
NM_000238.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 4.85

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:

KCNH2 (HGNC:):

KCNH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 23) in uniprot entity KCNH2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000238.4

BP4

Computational evidence support a benign effect (MetaRNN=0.18197843).

BS2

High AC in GnomAd4 at 5 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.1459G>A	p.Gly487Ser	missense_variant	6/15	ENST00000262186.10	NP_000229.1	Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNH2	ENST00000262186.10 linkuse as main transcript	c.1459G>A	p.Gly487Ser	missense_variant	6/15	1	NM_000238.4	ENSP00000262186.5		Q12809-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251452

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000694

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000880

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 29, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2015	p.Gly487Ser (GGC>AGC): c.1459 G>A in exon 6 of the KCNH2 (aka HERG) gene (NM_000238.2)The Gly487Ser variant in the KCNH2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gly487Ser results in a non-conservative amino acid substitution of a non-polar Glycine with a polar Serine at a position that is conserved across species. In silico analysis predicts Gly487Ser is probably damaging to the protein structure/function. Mutations in nearby residues (Ile489Phe, Ala490Thr, Ala490Pro, His492Tyr) have been reported in association with LQTS, supporting the functional importance of this region of the protein. Also, the Gly487Ser variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.With the clinical and molecular information available at this time, we cannot definitively determine if Gly487Ser is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The KCNH2 p.Gly147Ser variant was identified in 1 of 84 proband chromosomes (frequency: 0.012) from individuals with sudden unexpected death (Suktitipat_2017_PMID:28704380). The variant was also identified in dbSNP (ID: rs562875924) and ClinVar (classified as uncertain significance by Invitae and GeneDx). The variant was identified in control databases in 24 of 282842 chromosomes at a frequency of 0.00008485 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 7 of 10370 chromosomes (freq: 0.000675), South Asian in 7 of 30616 chromosomes (freq: 0.000229), African in 5 of 24954 chromosomes (freq: 0.0002), Other in 1 of 7220 chromosomes (freq: 0.000139), Latino in 1 of 35436 chromosomes (freq: 0.000028) and European (non-Finnish) in 3 of 129172 chromosomes (freq: 0.000023), but was not observed in the East Asian or European (Finnish) populations. The p.Gly147 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Long QT syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 29, 2024	This missense variant replaces glycine with serine at codon 487 of the KCNH2 protein. Computational prediction tool 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with sudden unexpected death (PMID: 28704380). This variant has also been identified in 24/282842 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 487 of the KCNH2 protein (p.Gly487Ser). This variant is present in population databases (rs562875924, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of KCNH2-related conditions (PMID: 28606196, 30327538). ClinVar contains an entry for this variant (Variation ID: 200342). 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. 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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 19, 2020

Variant summary: KCNH2 c.1459G>A (p.Gly487Ser) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of 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 9.1e-05 in 251452 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in KCNH2 causing Arrhythmia (9.1e-05 vs 0.0001), allowing no conclusion about variant significance. c.1459G>A has been reported in the literature in individuals affected with sudden unexpected death along with a frameshift mutation in CACNB2 (Suktitipat_2017) and Long QT Syndrome (McLeod_2017). These reports however, do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Long QT syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 17, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. 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 (LQTS; MIM#613688). Gain of function is also a known mechanism associated with short QT syndrome 1 (SQTS; MIM#609620) (OMIM, PMIDs: 10753933, 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 glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (26 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ion transport domain (NCBI, DECIPHER). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. The p.(Gly487Ala) has been reported as VUS for arrhythmia (ClinVar). p.(Gly487Cys) was identified in an individual with epilepsy and regarded as VUS (PMID: 31696929). p.(Gly487Arg) has been reported in a family undergoing genetic screening for sudden death, however the authors concluded that it does not cause severe heart disease (PMIDs: 22764740, 25947924). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported as both VUS and pathogenic, and in three individuals with LQTS or sudden death, as well as another sudden death individual who also has a variant in CACNB2 (VCGS, ClinVar, PMIDs: 26746457, 29192238, 30327538, 28606196, 2870438). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1004 - This variant has moderate functional evidence supporting normal protein function. Patch clamp analysis using transfected HEK293 cells showed p.(Gly487Ser), when co-expressed with wild type KCNH2, has a normal function of wildtype, with normal current density and channel deactivation ratio (PMID: 35688147, presented to AGHA MDT 29/7/22 by the AGHA Functional Genomics KCNH2 phenotyping group). (SB) 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

Nov 05, 2021

The p.G487S variant (also known as c.1459G>A), located in coding exon 6 of the KCNH2 gene, results from a G to A substitution at nucleotide position 1459. The glycine at codon 487 is replaced by serine, an amino acid with similar properties. This variant has been reported in sudden unexplained death (SUD) cohorts and in one individual reported to have long QT syndrome type 2; however, clinical details were limited, and one SUD case harbored an additional cardiac variant (McLeod KA et al. Cardiol Young, 2017 Sep;27:1271-1279; Bates K et al. Genet Med, 2019 06;21:1452-1456; Suktitipat B et al. PLoS One, 2017 Jul;12:e0180056). This variant has also been reported in exome and electronic medical record review cohorts with limited cardiovascular history provided (Van Driest SL et al. JAMA, 2016 Jan;315:47-57; Yamaguchi-Kabata Y et al. J Hum Genet, 2018 Feb;63:213-230). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, 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

Sep 08, 2021

- -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 10, 2024

This missense variant replaces glycine with serine at codon 487 of the KCNH2 protein. Computational prediction tool 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with sudden unexpected death (PMID: 28704380). This variant has also been identified in 24/282842 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

.;D;D

Eigen

Benign

0.011

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Uncertain

0.31

MutationAssessor

Benign

0.79

.;N;.

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.2

N;N;.

REVEL

Uncertain

0.54

Sift

Benign

0.21

T;T;.

Sift4G

Benign

0.45

T;T;T

Polyphen

0.053

B;P;.

Vest4

0.52

MVP

0.96

MPC

1.2

ClinPred

0.070

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.84

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.

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