ClinVar Miner

Submissions for variant NM_016203.4(PRKAG2):c.593C>T (p.Pro198Leu)

gnomAD frequency: 0.00005  dbSNP: rs41317142
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233598 SCV000290212 uncertain significance Lethal congenital glycogen storage disease of heart 2023-05-05 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. 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. ClinVar contains an entry for this variant (Variation ID: 241096). This variant has not been reported in the literature in individuals affected with PRKAG2-related conditions. This variant is present in population databases (rs41317142, gnomAD 0.004%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 198 of the PRKAG2 protein (p.Pro198Leu).
GeneDx RCV000519766 SCV000620696 uncertain significance not provided 2017-09-08 criteria provided, single submitter clinical testing The P198L variant of uncertain significance in the PRKAG2 gene has not been published in association with PRKAG2-related disorders to our knowledge. This variant is also not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, P198L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, while another missense variant at the same residue (P198A) has been reported in HGMD in association with HCM (Stenson et al., 2014; Alejandra Restrepo-Cordoba et al., 2017), the clinical significance of this variant also remains to be definitively determined.
Ambry Genetics RCV000619075 SCV000736832 uncertain significance Cardiovascular phenotype 2022-04-04 criteria provided, single submitter clinical testing The p.P198L variant (also known as c.593C>T), located in coding exon 4 of the PRKAG2 gene, results from a C to T substitution at nucleotide position 593. The proline at codon 198 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in an autism spectrum disorder cohort that had whole exome sequencing (Jiao J et al. J Mol Neurosci, 2020 Feb;70:219-229). This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health RCV001180377 SCV001345297 uncertain significance Cardiomyopathy 2023-09-29 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 198 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 been identified in 6/282504 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.
Fulgent Genetics, Fulgent Genetics RCV002487082 SCV002794126 uncertain significance Lethal congenital glycogen storage disease of heart; Hypertrophic cardiomyopathy 6; Wolff-Parkinson-White pattern 2021-09-06 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000519766 SCV000924912 uncertain significance not provided 2016-06-21 no assertion criteria provided provider interpretation We have seen this variant in an individual with LVNC. Testing was done at Invitae. Given the lack of case data we consider this variant to be uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been reported in the literature. The Invitae report notes: The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. The P198L variant was reported online in 1 of 60,507 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 4/2016). Specifically, the variant was observed in 1 of 5,780 Latino people. A different P198R variant at the same codon was reported online in 7 of 60,507 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 4/2016). Specifically, the variant was observed in 5 of 4,323 East Asian people and 2 of 33,224 non-Finnish European people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.
GenomeConnect - Invitae Patient Insights Network RCV003483592 SCV004228810 not provided PRKAG2 cardiac syndrome no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 01-04-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.