Submissions for variant NM_016203.4(PRKAG2):c.166G>A (p.Gly56Arg)

gnomAD frequency: 0.00004  dbSNP: rs397517266

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038925	SCV000062603	uncertain significance	not specified	2014-04-10	criteria provided, single submitter	clinical testing	The Gly56Arg variant in PRKAG2 has been previously identified by our laboratory in 1 individual with HCM, but was absent from large population studies. Glycine (Gly) at position 56 is not conserved in mammals or distantly related species, s uggesting that a change at this position may be tolerated. Other computational p rediction tools do not provide strong support for or against an impact to the pr otein. In summary, additional information is needed to fully assess the clinical significance of this variant.
Invitae	RCV000698517	SCV000827185	likely benign	Lethal congenital glycogen storage disease of heart	2024-01-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001178860	SCV001343413	uncertain significance	Cardiomyopathy	2022-11-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 56 of the PRKAG2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 34362124). This variant has also been reported in a cohort of sudden unexplained deaths (PMID: 29247119). This variant has been identified in 19/279446 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001270142	SCV001449038	uncertain significance	Hypertrophic cardiomyopathy	2019-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV002260602	SCV002540402	uncertain significance	not provided	2022-06-14	criteria provided, single submitter	clinical testing	Reported in association with HCM and sudden unexplained death (SUD) in published literature (Walsh et al., 2017; Lin et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29247119, 27532257)
PreventionGenetics, part of Exact Sciences	RCV003421954	SCV004117241	uncertain significance	PRKAG2-related condition	2023-07-23	criteria provided, single submitter	clinical testing	The PRKAG2 c.166G>A variant is predicted to result in the amino acid substitution p.Gly56Arg. This variant has been reported with uncertain significance in an individual with hypertrophic cardiomyopathy and in an individual from a sudden unexplained death cohort (Table S1B, Walsh R et al. 2017. PubMed ID: 27532257; Table S3, Lin Y et al. 2017. PubMed ID: 29247119). This variant is reported in 0.034% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-151483576-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.