Submissions for variant NM_016203.4(PRKAG2):c.1315A>G (p.Ile439Val)

gnomAD frequency: 0.00001  dbSNP: rs370257703

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038914	SCV000062592	uncertain significance	not specified	2012-04-20	criteria provided, single submitter	clinical testing	The Ile439Val variant (PRKAG2) has not been reported in the literature nor previ ously identified by our laboratory. It is located in the CBS domain region of t he PRKAG2 protein, where all pathogenic PRKAG2 variants have been identified to date (Oliveira 2003). Computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may not impact the pr otein, though this information is not predictive enough to rule out pathogenicit y. Additional information is needed to fully assess the clinical significance of the Ile439Val variant. PRKAG2 variants cause a heart specific non-lysosomal g lycogenosis with typical clinical onset in adolescence or the 3rd decade. Howev er, neonatal onset of hypertrophy has also been described (Burwinkel 2005).
GeneDx	RCV000766636	SCV000208953	uncertain significance	not provided	2024-06-03	criteria provided, single submitter	clinical testing	Has been reported as a variant of uncertain significance in association with HCM, DCM, or ARVC (PMID: 27532257); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 38254962, 27532257, 36243179)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV005054149	SCV000996375	uncertain significance	Hypertrophic cardiomyopathy 6	2017-04-27	criteria provided, single submitter	research	This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001348266	SCV001542560	uncertain significance	Lethal congenital glycogen storage disease of heart	2024-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 439 of the PRKAG2 protein (p.Ile439Val). This variant is present in population databases (rs370257703, gnomAD 0.003%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 45695). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Ambry Genetics	RCV004018881	SCV005010962	uncertain significance	Cardiovascular phenotype	2021-09-16	criteria provided, single submitter	clinical testing	The c.1315A>G (p.I439V) alteration is located in exon 12 (coding exon 12) of the PRKAG2 gene. This alteration results from a A to G substitution at nucleotide position 1315, causing the isoleucine (I) at amino acid position 439 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.