ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.971C>T (p.Pro324Leu) (rs750030887)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498314 SCV000589627 likely pathogenic not provided 2017-06-14 criteria provided, single submitter clinical testing The P324L variant has been reported in a patient with Pompe disease who harbored a second variant in the GAA gene (Laforêt et al. 2000). Functional studies found that P324L is associated with reduced acid alpha-glucosidase compared to wild-type (Flanagan et al. 2009). The P324L 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). The P324L variant is a semi-conservative amino acid substitution, that occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret this variant as likely pathogenic.
Counsyl RCV000670143 SCV000794962 uncertain significance Glycogen storage disease, type II 2017-10-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000670143 SCV000919373 likely pathogenic Glycogen storage disease, type II 2017-10-30 criteria provided, single submitter clinical testing Variant summary: The GAA c.971C>T (p.Pro324Leu) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/246128 control chromosomes at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). The variant was reported in a patient with severe infantile form of Pompe disease who carried a second second GAA mutation (W490X) and had 15% residual GAA activity (Laforet_2000). Additionally, a functional study performed in COS-7 cells showed the variant to have reduced GAA activity and GAA protein compared to wild-type (Flanagan_2009). In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as likely pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000670143 SCV001422623 uncertain significance Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The heterozygous p.Pro324Leu variant in GAA has been reported in 1 French individual with Glycogen Storage Disease II (PMID: 11071489), and has also been reported as a likely pathogenic variant by GeneDx and Integrated Genetics, and a VUS by Counsyl in ClinVar (Variation ID: 431990). This variant has been identified in 0.004% (1/24914) of African chromosomes, 0.003% (1/30616) of South Asian chromosomes and 0.0007754% (1/128970) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750030887). 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 with COS cells transfected with this variant provide some evidence that the p.Pro324Leu variant may impact GAA processing based on Western Blots (PMID: 19862843). 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. This variant was reported in combination with a rare nonsense variant and in an individual with Glycogen Storage Disease II (PMID: 11071489). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015).
Natera, Inc. RCV000670143 SCV001455598 likely pathogenic Glycogen storage disease, type II 2020-09-16 no assertion criteria provided clinical testing

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