rs199472948
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000238.4(KCNH2):c.1862G>A(p.Ser621Asn) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S621R) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 34)
Consequence
KCNH2
NM_000238.4 missense
NM_000238.4 missense
Scores
9
7
1
Clinical Significance
Conservation
PhyloP100: 6.00
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 18 ACMG points.
PM1
?
In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr7-150951530-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 3066169.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.98
PP5
?
Variant 7-150951531-C-T is Pathogenic according to our data. Variant chr7-150951531-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-150951531-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.1862G>A | p.Ser621Asn | missense_variant | 7/15 | ENST00000262186.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.1862G>A | p.Ser621Asn | missense_variant | 7/15 | 1 | NM_000238.4 | P1 |
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: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 10, 2019 | - - |
Long QT syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 14, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser621 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with KCNH2-related conditions (PMID: 20167303), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 25417810). 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 C0"). ClinVar contains an entry for this variant (Variation ID: 67299). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 11222472, 14998624, 24606995; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 621 of the KCNH2 protein (p.Ser621Asn). - |
Primary familial hypertrophic cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
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:11222472;PMID:11468227;PMID:11668638;PMID:14998624). 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
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
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.
Sift4G
Uncertain
D;D;D
Polyphen
P;P;.
Vest4
MutPred
0.90
.;Loss of disorder (P = 0.1512);.;
MVP
MPC
2.1
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