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. 12/21 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
Consequence
NM_000238.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNH2 | NM_000238.4 | c.1681G>C | p.Ala561Pro | missense_variant | 7/15 | ENST00000262186.10 | NP_000229.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNH2 | ENST00000262186.10 | c.1681G>C | p.Ala561Pro | missense_variant | 7/15 | 1 | NM_000238.4 | ENSP00000262186 | P1 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome Cov.: 36
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 05, 2018 | The 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 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: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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at