ClinVar Genomic variation as it relates to human health

The p.Leu248Pro variant in GAA has been reported in three individuals with glycogen storage disease II (PMID: 18425781, 29122469), and has been identified in 0.002% (2/128914) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1443844938). 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.Leu248Pro variant may impact protein function (PMID: 18425781). 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. Additionally, this variant has been reported in combination with a reported pathogenic variant in an individual with glycogen storage disease II (VariationID: 4027; PMID 29122469). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PP3 (Richards 2015).

Variant summary: GAA c.743T>C (p.Leu248Pro) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain (IPR031727) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251170 control chromosomes. c.743T>C has been reported in the literature in at-least two individuals, one of whom has a non-informative genotype (no second allele specified) (example, Kroos_2008) while the other is an adult with compound heterozygous genotype and late onset Pompe disease (example, Mori_2017). It has also been listed as having an unknown clinical severity rating in the Pompe variant database update (Nino_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in-vitro. The most pronounced variant effect results in 18% of normal acid alpha-glucosidase activity in cells while reporting 0% of normal activity in the medium (Kroos_2008). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.