ClinVar Miner

Submissions for variant NM_016203.4(PRKAG2):c.1367G>A (p.Arg456Gln)

gnomAD frequency: 0.00001  dbSNP: rs730880980
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766637 SCV000208955 uncertain significance not provided 2013-12-30 criteria provided, single submitter clinical testing p.Arg456Gln (CGA>CAA): c.1367 G>A in exon 12 of the PRKAG2 gene (NM_016203.3) The Arg456Gln variant in the PRKAG2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge.The Arg456Gln variant is a semi-conservative amino acid substitution as these residues share similar properties, but differ in size, charge, or other properties which may impact secondary structure. The Ag456 residue is conserved across species. In addition, in silico analysis predicts Arg456Gln is possibly damaging to the protein structure/function. The Arg456Gln 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. Nevertheless, no mutations affecting nearby residues have been reported in association with cardiomyopathy, indicating this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Arg456Gln is a disease-causing mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Baylor Genetics RCV001294191 SCV001483026 uncertain significance Hypertrophic cardiomyopathy 6 2018-11-11 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp RCV002516394 SCV003282811 uncertain significance Lethal congenital glycogen storage disease of heart 2022-02-27 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 expected to disrupt PRKAG2 protein function. ClinVar contains an entry for this variant (Variation ID: 181479). This variant has not been reported in the literature in individuals affected with PRKAG2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 456 of the PRKAG2 protein (p.Arg456Gln).
Ambry Genetics RCV004019923 SCV003889902 uncertain significance Cardiovascular phenotype 2023-02-23 criteria provided, single submitter clinical testing The c.1367G>A (p.R456Q) alteration is located in exon 12 (coding exon 12) of the PRKAG2 gene. This alteration results from a G to A substitution at nucleotide position 1367, causing the arginine (R) at amino acid position 456 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Clinical Genetics Laboratory, Skane University Hospital Lund RCV000766637 SCV005197271 uncertain significance not provided 2022-05-27 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000159013 SCV000280424 uncertain significance not specified 2011-12-28 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. PRKAG2 Arg456Gln (c.1367G>A) This variant is novel. In silico analysis with PolyPhen-2 predicts the variant to be possible damaging. Mutation Taster predicts this variant to be disease-causing. The arginine at codon 456 is conserved across species, as are neighboring amino acids. No other variants have been reported in association with disease at this codon or at nearby codons. The Arg456Gln variant is a semi-conservative amino acid substitution as these residues share similar properties, but differ in size, charge, or other properties which may impact secondary structure. In total the variant has not been seen in ~6,500 individuals from publicly available population datasets. There is no variation at codon 456 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 1/2/14). Note that this dataset does not match the patient's ancestry (Chinese). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/2/14).

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