Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2_SupportingPM5PP3_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 Genomes 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.
Verdict is Pathogenic. Variant got 11 ACMG points.
GnomAD3 genomesCov.: 34
Submissions by phenotype
|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
|not provided, no assertion 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. -|
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