ClinVar Miner

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

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Total submissions: 3
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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
Integrated Genetics/Laboratory Corporation of America 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.

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