Submissions for variant NM_016203.4(PRKAG2):c.1535A>T (p.Asn512Ile)

dbSNP: rs766113743

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000527257	SCV000640341	uncertain significance	Lethal congenital glycogen storage disease of heart	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 512 of the PRKAG2 protein (p.Asn512Ile). This variant is present in population databases (rs766113743, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PRKAG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 465340). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PRKAG2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001178595	SCV001343072	uncertain significance	Cardiomyopathy	2022-12-21	criteria provided, single submitter	clinical testing	This variant is located in 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 not been reported in individuals affected with PRKAG2-related disorders in the literature. This variant has been identified in 3/251492 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	RCV001755835	SCV001987924	uncertain significance	not provided	2020-06-16	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
All of Us Research Program, National Institutes of Health	RCV003999159	SCV004842206	uncertain significance	Hypertrophic cardiomyopathy	2024-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 512 of the PRKAG2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Ambry Genetics	RCV004024003	SCV005026394	uncertain significance	Cardiovascular phenotype	2024-01-27	criteria provided, single submitter	clinical testing	The p.N512I variant (also known as c.1535A>T), located in coding exon 14 of the PRKAG2 gene, results from an A to T substitution at nucleotide position 1535. The asparagine at codon 512 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.