ClinVar Miner

Submissions for variant NM_016203.4(PRKAG2):c.1592G>A (p.Arg531Gln) (rs121908991)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159019 SCV000208961 pathogenic not provided 2013-03-27 criteria provided, single submitter clinical testing p.Arg531Gln (CGG>CAG): c.1592 G>A in exon 15 of the PRKAG2 gene (NM_016203.3) The Arg531Gln mutation in the PRKAG2 gene has been reported in association with cardiomyopathy (Burwinkel B et al., 2005). This study identified Arg531Gln in three babies with severe congenital cardiomegaly and HCM and it was not identified in 190 control chromosomes. In one of the three reported infants, the Arg531Gln mutation was shown to further supporting its pathogenicity (Burwinkel B et al., 2005). Arg531Gln results in a semi-conservative amino acid substitution of a positively charged Arginine with a neutral, polar Glutamine at a position that is conserved across species. In silico analysis predicts Arg531Gln is damaging to the protein structure/function. Other missense mutations at this codon (Arg531Gly) and in a nearby codon (His530Arg) have been reported in association with HCM and WPW, and alter a functionally critical nucleotide binding site. In fact, functional studies have demonstrated that both Arg531Gln and Arg531Gly severely impair AMP and ATP binding and alter basal activity and phosphorylation of the AMP-activated protein kinase (Burwinkel B et al., 2005). Furthermore, The Arg531Gln mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, Arg531Gln in the PRKAG2 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Invitae RCV000007255 SCV000640343 pathogenic Glycogen storage disease of heart, lethal congenital 2017-06-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 531 of the PRKAG2 protein (p.Arg531Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals affected with nonlysosomal heart glycogenosis (PMID: 15877279) and hypertrophic cardiomyopathy (PMID: 25611685), with several affected individuals where the variant occurred de novo (PMID: 15877279, 25611685). ClinVar contains an entry for this variant (Variation ID: 6852). Experimental studies have shown that this missense change disrupts PRKAG2 protein function causing a gain of function (PMID: 15877279). A different missense substitution at this codon (p.Arg531Gly) has been determined to be pathogenic (PMID: 11748095, 14722619, 27621313). This suggests that the arginine residue is critical for PRKAG2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000007255 SCV000027451 pathogenic Glycogen storage disease of heart, lethal congenital 2005-06-01 no assertion criteria provided literature only
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038920 SCV000062598 pathogenic Hypertrophic cardiomyopathy 2012-07-18 no assertion criteria provided clinical testing The Arg531Gln variant in PRKAG2 has been reported in 3 infants with fatal congen ital heart glycogenosis, occurring de novo in one case, and was absent in 190 co ntrol chromosomes (Burwinkel 2005). In addition, this variant has been identifie d by our laboratory in 4 infants with HCM (including one individual who also had LVNC and features of glycogen storage disease) and appears to have occurred de novo in 2 of these cases (only one parent was available in the third case). Bioc hemical characterization of the Arg531Gln variant showed that it has a significa nt impact on protein function (Burwinkel 2005). In summary, the Arg531Gln varian t meets our criteria for pathogenicity (http://pcpgm.partners.org/LMM) based on de novo occurrence and functional studies.
Oxford Medical Genetics Laboratories,Oxford University Hospitals NHS Foundation Trust RCV000007255 SCV000926201 pathogenic Glycogen storage disease of heart, lethal congenital 2019-05-03 no assertion criteria provided clinical testing

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