Submissions for variant NM_016203.4(PRKAG2):c.455G>A (p.Arg152His)

gnomAD frequency: 0.00009  dbSNP: rs765374050

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474308	SCV000551582	likely benign	Lethal congenital glycogen storage disease of heart	2023-07-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617256	SCV000736848	uncertain significance	Cardiovascular phenotype	2022-06-07	criteria provided, single submitter	clinical testing	The p.R152H variant (also known as c.455G>A), located in coding exon 3 of the PRKAG2 gene, results from a G to A substitution at nucleotide position 455. The arginine at codon 152 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Harper AR et al. Nat Genet, 2021 02;53:135-142). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001078	SCV001158208	uncertain significance	not specified	2019-02-27	criteria provided, single submitter	clinical testing	The p.Arg152His variant (rs765374050) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.005 percent (identified on 13 out of 282,538 chromosomes), and has been reported to the ClinVar database (Variation ID: 410723). The arginine at position 152 is moderately conserved and computational analyses of the effects of the p.Arg152His variant on protein structure and function is deleterious (SIFT: damaging, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Arg152His variant with certainty.
Color Diagnostics, LLC DBA Color Health	RCV001185261	SCV001351436	uncertain significance	Cardiomyopathy	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 152 of the PRKAG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 33495597). This variant has been identified in 13/282538 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.
GeneDx	RCV001530039	SCV002072671	uncertain significance	not provided	2024-06-11	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function
All of Us Research Program, National Institutes of Health	RCV004001871	SCV004842292	uncertain significance	Hypertrophic cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 152 of the PRKAG2 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/282538 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001530039	SCV001744560	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001530039	SCV001951743	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001530039	SCV001971528	uncertain significance	not provided		no assertion criteria provided	clinical testing