ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1536C>A (p.Phe512Leu)

dbSNP: rs143491365
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000756197 SCV000582322 uncertain significance not provided 2017-05-11 criteria provided, single submitter clinical testing The F512L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The F512L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved in mammals, and missense variants in nearby residues (G514R; M515K) have been reported in the Human Gene Mutation Database in association with GSDII (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756197 SCV000883930 uncertain significance not provided 2017-07-07 criteria provided, single submitter clinical testing The p.Phe512Leu variant (rs143491365) has not been reported in the medical literature nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) Browser with an overall population frequency of 0.0004 percent (identified 1 out of 246,118 chromosomes). The phenylalanine at position 512 is moderately conserved considering twelve species from human to baker’s yeast (Alamut v2.9.0), and computational analyses of the effects of the p.Phe512Leu variant on protein structure and function is conflicting (SIFT: damaging, MutationTaster: polymorphism, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Phe512Leu variant with certainty.
Genome-Nilou Lab RCV001785637 SCV002027276 uncertain significance Glycogen storage disease, type II 2021-09-05 criteria provided, single submitter clinical testing
Invitae RCV001785637 SCV003340259 uncertain significance Glycogen storage disease, type II 2021-08-29 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 512 of the GAA protein (p.Phe512Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs143491365, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 429690). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 RCV003302728 SCV004001309 uncertain significance Cardiovascular phenotype 2023-04-03 criteria provided, single submitter clinical testing The p.F512L variant (also known as c.1536C>A), located in coding exon 9 of the GAA gene, results from a C to A substitution at nucleotide position 1536. The phenylalanine at codon 512 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic RCV000756197 SCV004224437 uncertain significance not provided 2023-01-18 criteria provided, single submitter clinical testing PM2
Natera, Inc. RCV001785637 SCV002092038 uncertain significance Glycogen storage disease, type II 2020-11-04 no assertion criteria provided clinical testing

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