Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Medical Affairs, |
RCV001003309 | SCV001161393 | pathogenic | Spinal muscular atrophy-progressive myoclonic epilepsy syndrome; Farber lipogranulomatosis | 2019-06-19 | criteria provided, single submitter | literature only | The clinical significance of variant c.518A>T is pathogenic based on the following rationale. The patient described in Teoh et al., 2017, DOI: 10.1542/peds.2016-1068, presented with a unique combined Farber disease/SMA-PME phenotype as described in Gene Reviews (https://www.ncbi.nlm.nih.gov/books/NBK488189/). Whole exome sequencing revealed compound heterozygous variants, c.518A>T and c.594_599dupCTTCAA, in the ASAH1 gene. The c.518A>T variant which causes a N173I transition was analyzed using in silico analysis tools. The Asparagine is highly conserved across multiple species. In silico tools overall supported pathogenicity with a PolyPhen2 score of 0.958 (probably damaging), a sorting intolerant from tolerant score of 0.1 (tolerated), and a combined annotation dependent development score of 23.1. The mutation was Sanger sequenced for confirmation and each parent was found to carry one of the variants supporting autosomal recessive inheritance. Acid ceramidase activity was measured using a leukocyte assay developed in the laboratory of Professor Edward Schuchman, at Mount Sinai, NY, and showed significantly decreased levels of enzyme activity when compared to the activity level in the parents verifying the pathogenicity of this variant. |