Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000367143 | SCV000472714 | uncertain significance | Farber lipogranulomatosis | 2017-04-28 | criteria provided, single submitter | clinical testing | The ASAH1 c.704G>A (p.Gly235Asp) variant is a missense variant that has been reported in one case study in which it is found in a compound heterozygous state with a frameshift variant in an infant who was initially diagnosed with juvenile idiopathic arthritis (Torcoletti et al. 2014). Control data are unavailable for the p.Gly235Asp variant, and it is not found in the 1000 Genomes Project, the Exome Sequencing Project or the Exome Aggregation Consortium despite being located in a region of good sequencing coverage. The variant is thus considered to be rare. Functional studies in cultured skin fibroblasts from the compound heterozygous individual demonstrated that the ceramide content was markedly elevated compared to wildtype, which is consistent with Farber disease. The evidence for this variant is limited. The p.Gly235Asp variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Farber lipogranulomatosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Gene |
RCV000853060 | SCV000994990 | likely pathogenic | not provided | 2019-07-26 | criteria provided, single submitter | clinical testing | The G235D variant has been reported in an infant with contractures and joint pain that progressed to subcutaneous nodules and hoarseness of the voice who harbored another variant in the ASAH1 gene (Tocoletti et al., 2014). The G235D variant is not observed in large population cohorts (Lek et al., 2016). The G235D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A different missense change at this residue (G235R) has been reported as pathogenic in the published literature in association with ASAH1-related disorders (Muramatsu et al., 2002; Bashyam et al., 2014). In summary, we interpret G235D as a likely pathogenic variant. |
| Clinical Genetics and Genomics, |
RCV000853060 | SCV001449804 | likely pathogenic | not provided | 2015-04-10 | criteria provided, single submitter | clinical testing |