Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Medical Affairs, |
RCV001003307 | SCV001161391 | pathogenic | Farber lipogranulomatosis | 2019-06-19 | criteria provided, single submitter | literature only | Variant c.760A>G is pathogenic. This variant has been identified in 6 Farber disease patients from 4 unrelated families. In Bonafe et al., 2015, DOI: 10.1002/art.39752, the patient (proband) and his 2 older sisters were diagnosed with mild Farber disease. In all three patients, the variant c.760A>G was identified using whole exome sequencing. Functional testing demonstrated acid ceramidase activity levels in the patient's cultured fibroblasts were ~7-8% of the normal activity found in control cells. In addition to Bonafe et al., 2015, variant c.760A>G has been identified in 3 additional unrelated individuals described by Li et al., 1999, DOI: 10.1006/geno.1999.5940, Ehlert et al., 2018, DOI: 10.1002/jimd.12043, and Kostik et al., DOI 10.1007/s10545-012-9573-z 2012. The Farber disease patient described in Li et al., 1999, underwent FLAG-tagged mutant protein expressed in COS1 cells. This patient demonstrated <10% AC enzyme activity verifying the result seen in Bonafe et al., 2015. The total number of Farber disease patients identified with variant c.760A>G and functional testing supports the clinical pathogenicity of this mutation. |
| Invitae | RCV003558631 | SCV004294550 | pathogenic | not provided | 2023-08-07 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ASAH1 function (PMID: 10610716). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ASAH1 protein function. ClinVar contains an entry for this variant (Variation ID: 812478). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 254 of the ASAH1 protein (p.Arg254Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Farber’s disease (PMID: 10610716, 26945816). It has also been observed to segregate with disease in related individuals. |