Submissions for variant NM_016203.4(PRKAG2):c.1304A>G (p.Asn435Ser)

gnomAD frequency: 0.00008  dbSNP: rs200589374

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000675709	SCV000203345	uncertain significance	not provided	2014-02-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000675709	SCV000208952	uncertain significance	not provided	2020-11-06	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 167533; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29121657)
Invitae	RCV000687199	SCV000814753	likely benign	Lethal congenital glycogen storage disease of heart	2024-01-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001191112	SCV001358808	uncertain significance	Cardiomyopathy	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 435 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 29/282876 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199317	SCV001370397	uncertain significance	Wolff-Parkinson-White pattern	2019-06-21	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. This variant was detected in homozygous state.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001191112	SCV002043486	uncertain significance	Cardiomyopathy	2022-03-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381485	SCV002689929	uncertain significance	Cardiovascular phenotype	2020-03-19	criteria provided, single submitter	clinical testing	The p.N435S variant (also known as c.1304A>G), located in coding exon 12 of the PRKAG2 gene, results from an A to G substitution at nucleotide position 1304. The asparagine at codon 435 is replaced by serine, an amino acid with highly similar properties. This variant has been reported to co-occur with a pathogenic mutation in the MYH7 gene in a family with hypertrophic cardiomyopathy (Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV000675709	SCV000801423	uncertain significance	not provided	2017-06-07	no assertion criteria provided	clinical testing