rs1805123

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_000238.4(KCNH2):c.2690A>T(p.Lys897Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000305 in 982,178 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K897R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 27)

Exomes 𝑓: 0.0000031 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNH2
NM_000238.4 missense, splice_region

Scores

Splicing: ADA: 0.09944

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.77

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 was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 14 uncertain in NM_000238.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-150948445-CT-G is described in ClinVar as [Pathogenic]. Clinvar id is 200658.Status of the report is criteria_provided_single_submitter, 1 stars.

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 Brugada syndrome, long QT syndrome, short QT syndrome, short QT syndrome type 1, long QT syndrome 2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH2	NM_000238.4 link	c.2690A>T	p.Lys897Met	missense_variant, splice_region_variant	Exon 11 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.2690A>T	p.Lys897Met	missense_variant, splice_region_variant	Exon 11 of 15	1	NM_000238.4	ENSP00000262186.5	Q12809-1
KCNH2	ENST00000330883.9 link	c.1670A>T	p.Lys557Met	missense_variant, splice_region_variant	Exon 7 of 11	1		ENSP00000328531.4	Q12809-2
KCNH2	ENST00000684241.1 link	n.3523A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 13

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

116930

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000305

AC:

AN:

982178

Hom.:

Cov.:

AF XY:

0.00000602

AC XY:

AN XY:

498550

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

18114

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

37990

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

17984

Gnomad4 EAS exome

AF:

0.0000612

AC:

AN:

16334

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

74438

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

30286

Gnomad4 NFE exome

AF:

0.00000269

AC:

AN:

743898

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

38798

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

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>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

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0.00

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116938

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0.00

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AN XY:

56512

Gnomad4 AFR

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Gnomad4 NFE

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Gnomad4 OTH

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0.00

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Alfa

AF:

0.00

Hom.:

11563

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:2

Jul 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 897 of the KCNH2 protein (p.Lys897Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 200480). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 23, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces lysine with methioin at codon 897 of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. -

not provided

Uncertain:1

Jan 04, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Lys897Met (AAG>ATG): c.2690 A>T in exon 11 of the KCNH2 (aka HERG) gene (NM_000238.2). The Lys897Met variant in the KCNH2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Lys897Met results in a non-conservative amino acid substitution of a positively charged Lysine with a non-polar Methionine at a position that is conserved across species. Mutations in nearby codons (Arg894Cys, Arg894Leu, Gly903Arg) have been reported in association with LQTS, supporting the functional importance of this region of the protein. Also, the NHLBI ESP Exome Variant Server reports Lys897Met was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, another missense change at this codon (Lys897Thr) has been reported as a polymorphism. With the clinical and molecular information available at this time, we cannot definitively determine if Lys897Met is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). -

Cardiac arrhythmia

Uncertain:1

Feb 16, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces lysine with methionine at codon 897 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with KCNH2-related disorders in the literature. This variant has not been identified 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

0.29

CardioboostArm

Benign

0.0096

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

.;D

Eigen

Benign

-0.019

Eigen_PC

Benign

-0.067

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.76

T;T

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.51

D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.7

.;L

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.7

N;N

REVEL

Pathogenic

0.66

Sift

Benign

0.049

D;T

Sift4G

Benign

0.13

T;T

Polyphen

0.97

D;B

Vest4

0.59

MutPred

0.26

.;Loss of ubiquitination at K897 (P = 0.0039);

MVP

0.88

MPC

0.32

ClinPred

0.78

GERP RS

-0.036

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.089

gMVP

0.78

Mutation Taster

=43/57

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.099

dbscSNV1_RF

Benign

0.36

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