rs199472934

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000238.4(KCNH2):​c.1790A>G​(p.Tyr597Cys) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 34)

Consequence

KCNH2
NM_000238.4 missense

Scores

11
7
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 2.21
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 Pathogenic. Variant got 16 ACMG points.

PM1
In a topological_domain Extracellular (size 42) in uniprot entity KCNH2_HUMAN there are 29 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, 0.959
PP5
Variant 7-150951603-T-C is Pathogenic according to our data. Variant chr7-150951603-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNH2NM_000238.4 linkuse as main transcriptc.1790A>G p.Tyr597Cys missense_variant 7/15 ENST00000262186.10 NP_000229.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNH2ENST00000262186.10 linkuse as main transcriptc.1790A>G p.Tyr597Cys missense_variant 7/151 NM_000238.4 ENSP00000262186 P1Q12809-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxNov 12, 2015The Y597C likely pathogenic variant in the KCNH2 gene has been reported previously in one individual referred for LQTS genetic testing, and was absent from 2,600 control alleles (Kapplinger et al., 2009). Additionally, Y597C was observed in other unrelated individuals referred for LQTS genetic testing at GeneDx and was classified in ClinVar as a variant of uncertain significance by another clinical laboratory (Landrum et al., 2014). The Y597C 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. The Y597C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved across species. Furthermore, functional studies show that the Y597C variant results in deficient protein trafficking (Anderson et al., 2014). Therefore, this variant is likely pathogenic. -
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 06, 2022This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 597 of the KCNH2 protein (p.Tyr597Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 19716085; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67277). 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: "Probably Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 12407082, 25417810). For these reasons, this variant has been classified as Pathogenic. -
Congenital long QT syndrome Other:1
not provided, no classification providedliterature onlyCardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust-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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.35
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
.;D;D
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.97
D;D;D
M_CAP
Pathogenic
0.79
D
MetaRNN
Pathogenic
0.96
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
.;H;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-8.5
D;D;.
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D;.
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.73
MutPred
0.83
.;Gain of catalytic residue at P596 (P = 0.0137);.;
MVP
0.99
MPC
2.4
ClinPred
1.0
D
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.87
gMVP
0.99

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.

Other links and lift over

dbSNP: rs199472934; hg19: chr7-150648691; API