Submissions for variant NM_016203.4(PRKAG2):c.554A>T (p.Glu185Val)

gnomAD frequency: 0.00003  dbSNP: rs397517274

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038946	SCV000062624	uncertain significance	not specified	2012-10-16	criteria provided, single submitter	clinical testing	The Glu185Val variant in PRKAG2 has not been reported in the literature nor prev iously identified by our laboratory. Computational analyses (biochemical amino a cid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide str ong support for or against an impact to the protein. Additional information is n eeded to fully assess the clinical significance of the Glu185Val variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531085	SCV000640347	likely benign	Lethal congenital glycogen storage disease of heart	2024-11-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001184217	SCV001350157	uncertain significance	Cardiomyopathy	2024-03-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with valine at codon 185 of the PRKAG2 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with cardiomyopathy (PMID: 32009526, 32646569) and in one individual affected with sudden unexpected death (PMID: 30878466). This variant has been identified in 11/251486 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	RCV001559913	SCV001782233	uncertain significance	not provided	2024-03-15	criteria provided, single submitter	clinical testing	Reported in individuals with cardiomyopathy, sudden infant death, and a PRKAG2-related phenotype; however, at least three of these individuals harbored variants in other genes (PMID: 30878466, 32646569, 32009526); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32646569, 32009526, 30878466)
All of Us Research Program, National Institutes of Health	RCV003996424	SCV004842277	uncertain significance	Hypertrophic cardiomyopathy	2024-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with valine at codon 185 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with cardiovascular disorder (Pottinger et al., 2019) and in an individual affected with sudden unexpected death (PMID: 30878466). This variant has been identified in 11/251486 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001559913	SCV005878619	uncertain significance	not provided	2024-10-22	criteria provided, single submitter	clinical testing	The PRKAG2 c.554A>T; p.Glu185Val variant (rs397517274, ClinVar Variation ID: 45724) is reported in the literature in individuals affected with cardiomyopathy and in a sudden infant death (Lopez-Sainz 2020, Pottinger 2020, Subbotina 2019). This variant is found in the general population with an overall allele frequency of 0.004% (11/251,486 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.491). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Lopez-Sainz A et al. Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis. J Am Coll Cardiol. 2020 Jul 14;76(2):186-197. PMID: 32646569. Pottinger TD et al. Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants. J Am Heart Assoc. 2020 Feb 4;9(3):e013808. PMID: 32009526. Subbotina E et al. Functional characterization of ABCC9 variants identified in sudden unexpected natural death. Forensic Sci Int. 2019 May;298:80-87. PMID: 30878466.