Submissions for variant NM_016203.4(PRKAG2):c.1592G>T (p.Arg531Leu)

dbSNP: rs121908991

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038921	SCV000062599	uncertain significance	Hypertrophic cardiomyopathy	2022-06-27	criteria provided, single submitter	clinical testing	The p.Arg531Leu variant in PRKAG2 has been reported in at least 2 individuals with HCM (Alfares 2015 PMID: 25611685, Walsh 2017 PMID: 27532257, Invitae pers. comm., LMM data, ClinVar Variation ID: 45701). It was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In addition, another variant involving this codon (p.Arg531Leu) is classified as pathogenic by our lab and this variant is located within the CBS domain region where all pathogenic PRKAG2 variants have been identified to date (Oliveira 2003 PMID: 14519435). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5, PS4_Supporting, PM2_Supporting, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000641181	SCV000762819	pathogenic	Lethal congenital glycogen storage disease of heart	2022-12-04	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Arg531 amino acid residue in PRKAG2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11748095, 14722619, 15877279, 25611685, 27621313). 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. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 531 of the PRKAG2 protein (p.Arg531Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25611685, 27532257). ClinVar contains an entry for this variant (Variation ID: 45701).
GeneDx	RCV002255264	SCV002526523	uncertain significance	not provided	2023-01-04	criteria provided, single submitter	clinical testing	Reported in patients with HCM in the published literature (Alfares et al., 2015; Walsh et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25611685, 27532257)
Color Diagnostics, LLC DBA Color Health	RCV003531937	SCV004359734	likely pathogenic	Cardiomyopathy	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 531 in the CBS domain 4 of the PRKAG2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257; communication with an external laboratory; ClinVar SCV000762819.4, SCV002526523.2). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon, p.Arg531Gln and p.Arg531Gly, are well documented to be disease-causing variants (ClinVar variation ID: 6852 and 6851), indicating that arginine at this position is important for PRKAG2 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000038921	SCV004830183	likely pathogenic	Hypertrophic cardiomyopathy	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 531 in the CBS domain 4 of the PRKAG2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257; communication with an external laboratory; ClinVar SCV000762819.4, SCV002526523.2). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon, p.Arg531Gln and p.Arg531Gly, are well documented to be disease-causing variants (ClinVar variation ID: 6852 and 6851), indicating that arginine at this position is important for PRKAG2 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.