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rs199472921

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000238.4(KCNH2):c.1681G>C(p.Ala561Pro) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A561T) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 34)

Consequence

KCNH2
NM_000238.4 missense

Scores

14
3
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 7.72
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 12 ACMG points.

PM1
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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 chr7-150951712-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 67229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 7-150951712-C-G is Pathogenic according to our data. Variant chr7-150951712-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 67230.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-150951712-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNH2NM_000238.4 linkuse as main transcriptc.1681G>C p.Ala561Pro missense_variant 7/15 ENST00000262186.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNH2ENST00000262186.10 linkuse as main transcriptc.1681G>C p.Ala561Pro missense_variant 7/151 NM_000238.4 P1Q12809-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsFeb 05, 2018The p.A561P pathogenic mutation (also known as c.1681G>C), located in coding exon 7 of the KCNH2 gene, results from a G to C substitution at nucleotide position 1681. The alanine at codon 561 is replaced by proline, an amino acid with highly similar properties. This alteration was detected in a proband with long QT syndrome (LQTS) with drug-induced torsades de pointes as well as in the proband's father and brother, both of whom exhibited prolonged QTc intervals (Bellocq C et al. Mol Pharmacol. 2004;66(5):1093-102). In vitro functional studies have reported that this alteration results in abnormal protein trafficking and altered ion channel function (Bellocq C et al. Mol Pharmacol. 2004;66(5):1093-102; Anderson CL et al. Nat Commun. 2014;5:5535; Jouni M et al. J Am Heart Assoc. 2015;4(9):e002159). Two disease-causing mutations, p.A561V and p.A561T, have been described in the same codon (Curran ME et al. Cell. 1995;80(5):795-803; Dausse E et al. J Mol Cell Cardiol. 1996;28(8):1609-15). In addition, internal structural analysis indicates that this alteration, which occurs in the S5 domain of the central pore, is structurally disruptive (Ambry internal data; Long SB et al. Nature. 2007;450(7168):376-82). Based on the supporting evidence, p.A561P is interpreted as a disease-causing mutation. -
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:15280442;PMID:15159330). 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
Pathogenic
1.0
CardioboostArm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.59
Cadd
Pathogenic
30
Dann
Uncertain
1.0
Eigen
Pathogenic
0.76
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-4.8
D;D;.
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D;.
Sift4G
Uncertain
0.0060
D;D;D
Polyphen
0.99
D;D;.
Vest4
0.97
MutPred
0.94
.;Loss of stability (P = 0.1365);.;
MVP
1.0
MPC
2.5
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.99
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.13
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: rs199472921; hg19: chr7-150648800; API