Submission Details

The relationship between the PSAP gene and atypical Gaucher disease due to saposin C deficiency (GDSAPC), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of September 6, 2022. PSAP encodes prosaposin (pSap), a precursor protein that is cleaved in the endosome to form saposins A-D, which are small glycoproteins involved in sphingolipid degradation via activating lysosomal hydrolases; saposin C activates glucocerebrosidase for the hydrolysis of glucosylceramide in lysosomes (as reviewed in PMID: 22652185). Among patients with GDSAPC, deficiency of saposin C results in impaired glucocerebrosidase activation, causing lysosomal accumulation of glucocerebroside (PMID: 20484222), which leads in the characteristic clinical manifestations of Gaucher’s disease which include hepatosplenomegaly, thrombocytopenia, bone lesions, anemia, and in some cases, neurologic anomalies (as reviewed in PMID: 15464415)

The disease mechanism of GDSAPC is loss of function. GDSAPC was first reported by Christomanou et al. in 1986 (PMID: 3024666) and the first report of biallelic variants in PSAP among GDSAPC cases was by Diaz-Font in 2005 (PMID: 15856305). Both case-level (genetic) and experimental evidence support the relationship between PSAP and GDSAPC. Reported causal variants include missense, nonsense, deletions, and splice-altering variants (PMID: 20484222, PMID: 15856305, PMID: 2060627, PMID: 17919309, PMID: 28457694, PMID: 35316504, PMID: 31061751, PMID: 35456468). In total, thirteen variants from nine probands in eight publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached.

Experimental evidence for the relationship between PSAP and GDSAPC includes: the biochemical function of the gene product (prosaposin) being consistent with the clinical and biochemical findings identified individuals with GDSAPC (PMID: 20484222, PMID: 22652185, PMID: 15464415); the biochemical and clinical features of PSAP knockout mice (PMID: 20015957); and partial rescue of central nervous system glucocerebrosidase accumulation and neurologic impairment via insertion of saposin C cDNA into PSAP knockout mice (PMID: 12208132). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.

In sum, PSAP is definitively associated with GDSAPC. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. Classification aproved by the Clingen Lysosomal Diseases Gene Curation Expert Panel on October 6, 2022 (SOP v9).