rs199472958
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000238.4(KCNH2):c.1888G>C(p.Val630Leu) variant causes a missense change. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V630A) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 34)
Consequence
KCNH2
NM_000238.4 missense
NM_000238.4 missense
Scores
10
7
2
Clinical Significance
Conservation
PhyloP100: 6.02
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 11 ACMG points.
PM1
In a intramembrane_region Pore-forming; Name=Segment H5 (size 20) in uniprot entity KCNH2_HUMAN there are 23 pathogenic changes around while only 0 benign (100%) 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 chr7-150951504-A-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969
PP5
Variant 7-150951505-C-G is Pathogenic according to our data. Variant chr7-150951505-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67318.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=1}. Variant chr7-150951505-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.1888G>C | p.Val630Leu | missense_variant | 7/15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
Cov.:
34
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome Cov.: 34
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Long QT syndrome 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 02, 2020 | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with long QT syndrome type 2. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (7 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. Highly conserved, minor amino acid change. (SP) 0600 - Variant is located in the annotated pore domain (PDB). (I) 0703 – Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. p.(Val630Ile) has two likely pathogenic entries in ClinVar and has been classified as pathogenic in a sudden arrhythmic death patient (PMID: 28449774). p.(Val630Ala) has been reported in two LQTS patients, one being de novo (PMID: 15840476, 9693036). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individuals. This variant has been identified in a Japanese LQTS patient (PMID: 9024139) and has one ClinVar entry (no classification provided). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional evidence shows that this variant decreases slope conductance and negatively shifts steady-state inactivation (PMID: 9721698). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 27, 2022 | 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. This variant disrupts the p.Val630 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9693036, 16432067, 23303164). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 9721698, 16432067, 23303164). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 67318). This missense change has been observed in individual(s) with long QT syndrome (PMID: 9024139). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 630 of the KCNH2 protein (p.Val630Leu). - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular 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:9024139;PMID:16432067). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
.;M;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.
Sift4G
Uncertain
D;D;D
Polyphen
P;P;.
Vest4
MutPred
0.85
.;Loss of sheet (P = 0.0817);.;
MVP
MPC
2.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at