Submissions for variant NM_016203.4(PRKAG2):c.1589A>G (p.His530Arg)

dbSNP: rs267606977

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159018	SCV000208960	pathogenic	not provided	2012-03-08	criteria provided, single submitter	clinical testing	p.His530Arg (CAT>CGT:c.1598 A>G in exon 15 of the PRKAG2 gene (NM_016203.3) The His530Arg mutation in the PRKAG2 gene has been reported previously in one individual with childhood-onset HCM, and this mutation was absent from >1,000 control alleles. In addition, the NHLBI ESP Exome Variant Server reports His530Arg was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Although His530Arg results in a conservative substitution of one positively charged amino acid for another, the His530 residue is conserved across species. Mutations in a neighboring codon (Arg531Gln, Arg531Gly) have also been reported in association with PRKAG2-related phenotypes, supporting the functional importance of this region of the protein. In summary, the presence of His530Arg in the PRKAG2 gene is consistent with a diagnosis of a PRKAG2-related cardiomyopathy and/or Wolff-Parkinson-White (WPW) syndrome. The variant is found in HCM panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000813711	SCV000954081	pathogenic	Lethal congenital glycogen storage disease of heart	2024-04-17	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 530 of the PRKAG2 protein (p.His530Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PRKAG2-related cardiac conditions, including hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome (PMID: 18403758, 26085771, 28431061; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6854). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRKAG2 protein function. Experimental studies have shown that this missense change affects PRKAG2 function (PMID: 27573176). For these reasons, this variant has been classified as Pathogenic.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852579	SCV000995280	pathogenic	Hypertrophic cardiomyopathy	2018-02-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399313	SCV002705691	pathogenic	Cardiovascular phenotype	2021-10-11	criteria provided, single submitter	clinical testing	The p.H530R pathogenic mutation (also known as c.1589A>G), located in coding exon 15 of the PRKAG2 gene, results from an A to G substitution at nucleotide position 1589. The histidine at codon 530 is replaced by arginine, an amino acid with highly similar properties. This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM), Wolff-Parkinson-White syndrome, and other cardiac arrhythmias, and it has been shown to segregate with disease in affected family members (Morita H et al. N Engl J Med, 2008 May;358:1899-908; Epicoco G et al. JACC Clin Electrophysiol, 2018 10;4:1377-1378; Aggarwal V et al. Ann Pediatr Cardiol;8:153-6; Xie C et al. Cell Res, 2016 Oct;26:1099-1111; Thevenon J et al. Europace, 2017 Apr;19:651-659; Lu C et al. J Transl Med, 2018 08;16:241). Functional studies in transgenic mouse models demonstrated consistent PRKAG2-related cardiac findings, including significant glycogen accumulation (Xie C et al. Cell Res, 2016 Oct;26:1099-1111). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000007257	SCV000027453	pathogenic	Hypertrophic cardiomyopathy 6	2008-05-01	no assertion criteria provided	literature only