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rs1805123

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

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. K897T) has been classified as Benign.

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

4
5
9
Splicing: ADA: 0.09944
2

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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNH2NM_000238.4 linkuse as main transcriptc.2690A>T p.Lys897Met missense_variant, splice_region_variant 11/15 ENST00000262186.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNH2ENST00000262186.10 linkuse as main transcriptc.2690A>T p.Lys897Met missense_variant, splice_region_variant 11/151 NM_000238.4 P1Q12809-1
KCNH2ENST00000330883.9 linkuse as main transcriptc.1670A>T p.Lys557Met missense_variant, splice_region_variant 7/111 Q12809-2
KCNH2ENST00000684241.1 linkuse as main transcriptn.3523A>T splice_region_variant, non_coding_transcript_exon_variant 9/13

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
116930
Hom.:
0
Cov.:
27
FAILED QC
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:
3
AN:
982178
Hom.:
0
Cov.:
28
AF XY:
0.00000602
AC XY:
3
AN XY:
498550
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000612
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000269
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
116938
Hom.:
0
Cov.:
27
AF XY:
0.00
AC XY:
0
AN XY:
56512
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:
0.00
Gnomad4 OTH
AF:
0.00

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
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthMar 23, 2023Variant 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. -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 09, 2022Algorithms 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. ClinVar contains an entry for this variant (Variation ID: 200480). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. This variant is not present in population databases (gnomAD no frequency). 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). -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 04, 2017p.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
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 16, 2023This 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
D
BayesDel_noAF
Uncertain
0.050
Cadd
Benign
23
Dann
Uncertain
0.99
Eigen
Benign
-0.019
Eigen_PC
Benign
-0.067
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.76
T;T
M_CAP
Pathogenic
0.83
D
MetaRNN
Uncertain
0.51
D;D
MetaSVM
Pathogenic
0.86
D
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.63
T
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
D
GERP RS
-0.036
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9
Varity_R
0.089
gMVP
0.78

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.

Other links and lift over

dbSNP: rs1805123; hg19: chr7-150645534; API