Submissions for variant NM_000891.3(KCNJ2):c.431G>A (p.Gly144Asp)

dbSNP: rs199473377

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644780	SCV000766494	pathogenic	Andersen Tawil syndrome; Short QT syndrome type 3	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 144 of the KCNJ2 protein (p.Gly144Asp). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly144 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11371347, 12163457, 12909315, 14522976, 22002906, 22589293). 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 KCNJ2 function (PMID: 22589293). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ2 protein function. ClinVar contains an entry for this variant (Variation ID: 67574). This missense change has been observed in individual(s) with Anderson-Tawil syndrome and catecholaminergic polymorphic ventricular tachycardia (PMID: 20382953, 22589293, 23595086). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).
GeneDx	RCV001775567	SCV002013541	pathogenic	not provided	2021-04-20	criteria provided, single submitter	clinical testing	Reported in an individual with catecholaminergic polymorphic ventricular tachycardia, syncope, and aborted cardiac arrest (Kimura et al., 2012); Published functional studies demonstrate impaired channel function with dominant negative current reduction (Kimura et al., 2012); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29353185, 24025405, 23595086, 20382953, 22589293, 22581653)
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058312	SCV000089832	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported in the following publications (PMID:20382953).
GenomeConnect - Invitae Patient Insights Network	RCV001535632	SCV001749660	not provided	Andersen Tawil syndrome; Short QT syndrome type 3; Atrial fibrillation, familial, 9		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 12-08-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
GenomeConnect, ClinGen	RCV001824594	SCV002075172	not provided	Andersen Tawil syndrome; Short QT syndrome type 1; Atrial fibrillation, familial, 1		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 05-29-2019 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.