Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000641187 | SCV000762825 | pathogenic | Lethal congenital glycogen storage disease of heart | 2023-12-19 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 302 of the PRKAG2 protein (p.Arg302Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of PRKAG2-related conditions (PMID: 32259713; Invitae). ClinVar contains an entry for this variant (Variation ID: 533881). 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 PRKAG2 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg302 amino acid residue in PRKAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14722619, 15611370, 16836667, 20031621, 23992123, 25997934). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV002369682 | SCV002688509 | likely pathogenic | Cardiovascular phenotype | 2022-02-23 | criteria provided, single submitter | clinical testing | The p.R302P variant (also known as c.905G>C), located in coding exon 7 of the PRKAG2 gene, results from a G to C substitution at nucleotide position 905. The arginine at codon 302 is replaced by proline, an amino acid with dissimilar properties. This variant has been detected in several individuals with presentations consistent with PRKAG2-related disease, including hypertrophic cardiomyopathy (HCM) and arrhythmia (Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10; Hu D et al. EBioMedicine, 2020 Apr;54:102723; Ambry internal data). Another alteration at the same codon, p.R302Q (c.905G>A), has been shown to impact protein function in both in vitro and in vivo functional studies (Scott et al. J Clin Invest. 2004 Jan;113:274-84; Sidhu et al. Circulation. 2005 Jan;111:21-9; Folmes et al. Circ Cardiovasc Genet. 2009 Oct;2:457-66; Zhang et al. J Cardiol. 2013 Oct;62:241-8; Thorn et al. EJNMMI Res. 2013;3:48), and has been seen to segregate with disease in multiple unrelated families described to have Wolff-Parkinson-White syndrome, cardiac conduction system disease, and HCM, or some combination of those presentations (Gollob et al. N Engl J Med. 2001 Jun;344(24):1823-31; Arad et al. J Clin Invest. 2002 Feb;109(3):357-62; Sternick et al. J Cardiovasc Electrophysiol. 2006 Jul; 17(7):724-32; Charron et al. Europace. 2007 Aug;9:597-600; Tan et al. Circ Arrhythm Electrophysiol. 2008 Oct;1:276-81; Thevenon J et al. Europace, 2017 Apr;19:651-659). The p.R302P (c.905G>C) variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |