Submissions for variant NM_016203.4(PRKAG2):c.313G>A (p.Val105Met)

gnomAD frequency: 0.00020  dbSNP: rs397517269

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038936	SCV000062614	uncertain significance	not specified	2016-05-27	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Val105Met var iant in PRKAG2 has been identified by our laboratory in 1 individual with HCM an d ventricular tachycardia and 1 individual with HCM/RCM. Both of these individua ls carried a likely pathogenic variant in another gene. This variant has been id entified in 5/66212 European chromosomes by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs397517269). Valine (Val) at positio n 105 is not conserved in mammals or evolutionarily distant species and 2 mammal s (elephant and platypus) carry a methionine (Met) at this position, suggesting that this change may be tolerated. Additional computational prediction tools sug gest that this variant may not impact the protein, though this information is no t predictive enough to rule out pathogenicity. In addition, this variant is loca ted outside the CBS domain region where all pathogenic PRKAG2 variants have been identified(Oliveira 2003). In summary, while the clinical significance of the p .Val105Met variant is uncertain, these data suggest that it is more likely to be benign.
GeneDx	RCV000767091	SCV000535037	uncertain significance	not provided	2023-02-27	criteria provided, single submitter	clinical testing	Identified in a patient with HCM in published literature (Mademont-Soler et al., 2017); this patient harbored additional cardiogenetic variants; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28771489)
Color Diagnostics, LLC DBA Color Health	RCV001177608	SCV001341847	likely benign	Cardiomyopathy	2020-11-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001224749	SCV001396968	likely benign	Lethal congenital glycogen storage disease of heart	2024-12-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018884	SCV001444056	uncertain significance	Cardiovascular phenotype	2021-11-10	criteria provided, single submitter	clinical testing	The c.313G>A (p.V105M) alteration is located in exon 3 (coding exon 3) of the PRKAG2 gene. This alteration results from a G to A substitution at nucleotide position 313, causing the valine (V) at amino acid position 105 to be replaced by a methionine (M). The alteration is ultra rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.313G>A alteration was observed in 0.012% (32/276916) total alleles studied. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.V105 amino acid is somewhat well conserved in available vertebrate species. Both the elephant and the platypus share the proband's methionine as the reference allele at the 105 position. In silico prediction is conflicting:_x000D_ _x000D_ The p.V105M alteration is predicted to be benign by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.