Submissions for variant NM_016203.4(PRKAG2):c.1687C>T (p.Gln563Ter)

gnomAD frequency: 0.00001  dbSNP: rs397517267

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038926	SCV000062604	uncertain significance	not specified	2013-09-26	criteria provided, single submitter	clinical testing	The Gln563X variant in PRKAG2 has now been identified by our laboratory in 1 Cau casian with HCM and 1 Caucasian with infantile-onset DCM. It was not identified in large population studies. This nonsense variant leads to a premature termina tion codon at position 563 and is predicted to lead to a truncated protein, resu lting in the loss of the last 7 amino acids. However, it is unclear whether the variant would impact the protein function. In summary, additional information is needed to fully assess the clinical significance of this variant.
Invitae	RCV000470168	SCV000551573	uncertain significance	Lethal congenital glycogen storage disease of heart	2023-07-13	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 45705). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257; Invitae). This variant is present in population databases (rs397517267, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Gln563*) in the PRKAG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the PRKAG2 protein.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845392	SCV000987453	uncertain significance	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003531938	SCV004359730	uncertain significance	Cardiomyopathy	2023-08-04	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 16 of the PRKAG2 gene, creating a premature translation stop signal in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a truncated protein. 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: 27532257). This variant has been identified in 2/249374 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.