rs1060500659

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000238.4(KCNH2):​c.2312A>G​(p.His771Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 30)

Consequence

KCNH2
NM_000238.4 missense

Scores

10
6
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 8.01
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 7 ACMG points.

PM1
In a binding_site (size 100) in uniprot entity KCNH2_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000238.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.905
PP5
Variant 7-150950254-T-C is Pathogenic according to our data. Variant chr7-150950254-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 405338.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNH2NM_000238.4 linkc.2312A>G p.His771Arg missense_variant 9/15 ENST00000262186.10 NP_000229.1 Q12809-1Q15BH2A0A090N8Q0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNH2ENST00000262186.10 linkc.2312A>G p.His771Arg missense_variant 9/151 NM_000238.4 ENSP00000262186.5 Q12809-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
38
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 01, 2023The p.H771R variant (also known as c.2312A>G), located in coding exon 9 of the KCNH2 gene, results from an A to G substitution at nucleotide position 2312. The histidine at codon 771 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in individuals with long QT syndrome (LQTS), including several affected members from one family, as well as in a LQTS clinical genetic testing cohort with limited clinical details provided (Ambry internal data; Stattin EL et al. BMC Cardiovasc Disord, 2012 Oct;12:95; Bennett JS et al. Pediatr Cardiol, 2019 Dec;40:1679-1687). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 06, 2024Variant summary: KCNH2 c.2312A>G (p.His771Arg) results in a non-conservative amino acid change located in the Cyclic nucleotide-binding domain (IPR000595) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250896 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2312A>G has been reported in the literature in individuals affected with Long QT syndrome (Stattin_2012, Bennett_2019). These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 31535183, 37324772, 34309407, 23098067). ClinVar contains an entry for this variant (Variation ID: 405338). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 21, 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 405338). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 23098067, 31535183; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 771 of the KCNH2 protein (p.His771Arg). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
.;D;T
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.91
D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Benign
1.5
.;L;.
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-7.8
D;D;.
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0010
D;D;.
Sift4G
Benign
0.17
T;T;T
Polyphen
0.75
P;P;.
Vest4
0.93
MutPred
0.51
.;Loss of glycosylation at T768 (P = 0.0964);.;
MVP
0.99
MPC
2.4
ClinPred
1.0
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.88
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.85
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.85
Position offset: 5

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: rs1060500659; hg19: chr7-150647342; API