Submissions for variant NM_016203.4(PRKAG2):c.1267C>A (p.Gln423Lys)

gnomAD frequency: 0.00012  dbSNP: rs147349145

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000234404	SCV000290201	likely benign	Lethal congenital glycogen storage disease of heart	2024-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000766390	SCV000573467	uncertain significance	not provided	2017-02-20	criteria provided, single submitter	clinical testing	The Q423K variant of uncertain significance in the PRKAG2 gene has not been published as pathogenic nor benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In silico analysis is inconsistent in its predictions as to whether or not Q423K is damaging to the protein structure/function. This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution also occurs at a position that is conserved in mammals; however, K423 is tolerated in at least two non-mammalian species. Furthermore, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with PRKAG2-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770260	SCV000901692	likely benign	Cardiomyopathy	2020-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770260	SCV001359096	likely benign	Cardiomyopathy	2022-01-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003343613	SCV004073784	uncertain significance	Cardiovascular phenotype	2023-08-25	criteria provided, single submitter	clinical testing	The p.Q423K variant (also known as c.1267C>A), located in coding exon 12 of the PRKAG2 gene, results from a C to A substitution at nucleotide position 1267. The glutamine at codon 423 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in cardiomyopathy cohorts; however, clinical details were limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203; Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038912	SCV000062590	uncertain significance	not specified	2008-03-01	no assertion criteria provided	clinical testing
Blueprint Genetics	RCV000157423	SCV000207164	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-10-27	no assertion criteria provided	clinical testing