Submissions for variant NM_177924.5(ASAH1):c.502G>T (p.Gly168Trp)

dbSNP: rs1421841663

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Medical Affairs, Dicerna Pharmaceuticals	RCV001003306	SCV001161390	pathogenic	Farber lipogranulomatosis	2019-06-19	criteria provided, single submitter	literature only	Variant c.502G>T has been classified as pathogenic. The patient described in Cvitanovic-Sojat et al., 2011, doi:10.1016/j.ejpn.2010.06.002, was diagnosed with Type 1 Farber disease symptoms described in Gene Reviews (https://www.ncbi.nlm.nih.gov/books/NBK488189/). Microscopic examination of subcutaneous and periarticular tissues showed the accumulation of macrophages, histiocytes, foam cells and PAS-positive material which is indicative of Farber disease. Homozygous c.502G>T variants were discovered through whole genome sequencing and confirmed at the cDNA level. A ceramide loading test was carried out using intact cultured skin fibroblasts. In the patient's cells, undegraded lysosomal ceramide represented 56% of radioactive sphingomyelin metabolites, compared to 2-7.5% in control cells. Acid ceramidase deficiency was confirmed using an in vitro assay measuring enzyme activity in fibroblast lysates. The patient's ceramidase activity was found to be undetectable [normal range 0.011-0.084 nmol/h/mg protein (n=9); mean 0.047]. Other lysosomal enzymes were within the normal range.