Submissions for variant NM_016203.4(PRKAG2):c.704T>G (p.Leu235Arg)

gnomAD frequency: 0.00007  dbSNP: rs751094298

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465041	SCV000551578	benign	Lethal congenital glycogen storage disease of heart	2024-10-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001181139	SCV001346226	uncertain significance	Cardiomyopathy	2023-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with arginine at codon 235 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 8/191708 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.
GeneDx	RCV001553387	SCV001774247	uncertain significance	not provided	2021-02-15	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#410720; Landrum et al., 2016)
Ambry Genetics	RCV002365655	SCV002662105	uncertain significance	Cardiovascular phenotype	2022-12-12	criteria provided, single submitter	clinical testing	The p.L235R variant (also known as c.704T>G), located in coding exon 5 of the PRKAG2 gene, results from a T to G substitution at nucleotide position 704. The leucine at codon 235 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001181139	SCV003837926	uncertain significance	Cardiomyopathy	2023-02-21	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224290	SCV003920351	uncertain significance	Lethal congenital glycogen storage disease of heart; Hypertrophic cardiomyopathy 6; Wolff-Parkinson-White pattern	2021-03-30	criteria provided, single submitter	clinical testing	PRKAG2 NM_016203.3 exon 5 p.Leu235Arg (c.704T>G): This variant has not been reported in the literature but is present in 0.04% (7/15616) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/7-151329205-A-C). This variant is present in ClinVar (Variation ID:410720). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.