Description
The p.Ser235Pro variant in GBA has been reported in at least 6 individuals with Gaucher disease (PMID: 12204005, 28727984, 22526844, 10796875, 10649495) and has been identified in 0.006% (2/34582) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1064644). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 21072) as pathogenic by Integrated Genetics and Shahid Beheshti University of Medical Sciences. In vitro functional studies provide some evidence that the p.Ser235Pro variant may impact protein function (PMID: 22526844). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 2 affected homozygotes and in combination with reported pathogenic variants in 4 individuals with Gaucher disease increases the likelihood that the p.Ser235Pro variant is pathogenic (VariationID: 4288, 4290, 65570; PMID: 12204005, 28727984, 22526844, 10796875, 10649495). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on its presence in affected homozygotes and compound heterozygotes, functional studies, and low frequency in the general population. ACMG/AMP Criteria applied: PM3_strong, PS3, PM2 (Richards 2015).
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
