chr17-80110825-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000152.5(GAA):c.1536C>A(p.Phe512Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000152.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251154Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135864
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461830Hom.: 0 Cov.: 37 AF XY: 0.00000688 AC XY: 5AN XY: 727214
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74322
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Uncertain:3
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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. -
not provided Uncertain:3
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. -
PM2 -
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. -
Cardiovascular phenotype Uncertain:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at