Submissions for variant NM_016203.4(PRKAG2):c.569G>A (p.Arg190His)

gnomAD frequency: 0.00001  dbSNP: rs551795395

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158999	SCV000208940	uncertain significance	not provided	2014-06-22	criteria provided, single submitter	clinical testing	p.Arg190His (CGC>CAC): c.569 G>A in exon 4 of the PRKAG2 gene (NM_016203.3) A variant of unknown significance has been identified in the PRKAG2 gene. The R190H variant has not been published as a mutation or as a benign polymorphism to our knowledge. The R190H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, this substitution occurs at a position that is conserved across species. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the R190H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, no missense mutations in nearby residues have been reported in association with a PRKAG2-related disorder, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in HCM panel(s).
Color Diagnostics, LLC DBA Color Health	RCV003532003	SCV004359756	uncertain significance	Cardiomyopathy	2024-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 190 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 PRKAG2-related disorders in the literature. This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003764998	SCV004630579	uncertain significance	Lethal congenital glycogen storage disease of heart	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 190 of the PRKAG2 protein (p.Arg190His). This variant is present in population databases (rs551795395, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PRKAG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 181470). 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.