Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Medical Affairs, |
RCV001003299 | SCV001161382 | pathogenic | Farber lipogranulomatosis | 2019-06-19 | criteria provided, single submitter | literature only | Variant c.410_411delAT has been classified as pathogenic using the following rationale. Variant c.410_411delAT described in Torcoletti et al, 2014,doi:10.1093/rheumatology/keu010 was identified in a caucasian, male patient diagnosed with characteristic Farber disease symptoms consistent with Type 1 Farber disease according to Gene Reviews (https://www.ncbi.nlm.nih.gov/books/NBK488189/). Biopsy and microscopic examination of subcutaneous nodules and periarticular tissue showed an accumulation of macrophages and foamy (lipid-filled) histiocytes with broad cytoplasm arranged in clusters which is characteristic of Farber disease. Analysis of the ASAH1 gene by direct sequencing of exons and adjacent intronic sequences identified the presence in combined heterozygosis of a 2 bp deletion (c.410-411delAT) with the subsequent creation of a premature stop codon in position 137 (p.Tyr137Xfs). Functional evidence demonstrates ceramide content in cultured skin fibroblasts was markedly elevated (22.87 nM/mg; 15-fold above control), consistent with Farber disease. The patient was treated with HCST as the only available treatment option for Farber disease. All Farber symptoms resolved shortly after treatment. In addition, one unrelated patient has been identified with the same variant, Ehlert et al., 2017, DOI: 10.1002/jimd.12043 lending further support for this variant's pathogenicity. |
| Labcorp Genetics |
RCV001860533 | SCV002238590 | pathogenic | not provided | 2023-09-10 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Tyr137*) in the ASAH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASAH1 are known to be pathogenic (PMID: 24164096, 24355074). This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Farber disease (PMID: 30815900). ClinVar contains an entry for this variant (Variation ID: 812471). For these reasons, this variant has been classified as Pathogenic. |
| Prevention |
RCV004553550 | SCV004108909 | pathogenic | ASAH1-related disorders | 2023-05-01 | criteria provided, single submitter | clinical testing | The ASAH1 c.458_459delAT variant is predicted to result in premature protein termination (p.Tyr153*). Using an alternate transcript (NM_177924), this variant is also referred to as c.410_411delAT (p.Tyr137fs). This variant was reported in the compound heterozygous state in an individual with Farber disease (Patient 08, Ehlert et al. 2019. PubMed ID: 30815900). This variant is reported in 0.0019% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-17922011-CAT-C). Loss of function variants in ASAH1 have been reported as causative of disease. This variant is interpreted as pathogenic. |