ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.871C>T (p.Leu291Phe)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001228970 SCV001401400 uncertain significance Glycogen storage disease, type II 2019-11-03 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 291 of the GAA protein (p.Leu291Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs773417785, ExAC 0.01%). This variant has been observed in individual(s) with Pompe disease (PMID: 31086307, 25526786). This variant has been reported to affect GAA protein function (PMID: 22644586). This variant disrupts the p.Leu291 amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 25213570), which suggests that this may be a clinically significant amino acid residue. 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.
Broad Institute Rare Disease Group,Broad Institute RCV001228970 SCV001422851 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Leu291Phe variant in GAA has been reported in 3 individuals with glycogen storage disease II (PMID: 30737479, 25526786, 18425781), and has been identified in 0.006% (1/15678) of African chromosomes and 0.006% (7/110146) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs773417785). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies using COS cells transfected with the variant provide some evidence that the p.Leu291Phe variant may impact protein function (PMID: 22644586). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual heterozygous for this variant is highly specific for glycogen storage disease II based on the absence of any known pseudodeficiency alleles and GAA enzyme activity in lymphocytes being <10% of wild type, consistent with disease (PMID: 30737479). Two additional pathogenic and likely pathogenic variants, resulting in a different amino acid change at the same position, p.Leu291Pro and p.Leu291His, have been reported in association with disease in the literature (PMID: 18458862, 22644586, 18425781). Additionally, the homozygous occurrence of this variant (PMID: 30737479), as well as the presence of this variant in combination with reported pathogenic variant p.Trp746Cys (VariationID: 265160; PMID 25526786), in individuals with glycogen storage disease II increases the likelihood that the p.Leu291Phe variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on in vitro functional studies, a patient with a phenotype highly specific for the disease, the presence of other pathogenic variants at the same location, and homozygous occurrence in an affected individual with another pathogenic variant. ACMG/AMP Criteria applied: PS3, PM2, PM3_supporting, PP4_moderate, PP3 (Richards 2015).

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