Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Medical Affairs, |
RCV001003337 | SCV001161422 | likely pathogenic | Farber lipogranulomatosis | 2019-07-01 | criteria provided, single submitter | literature only | Variant c.1098+1G>T is likely pathogenic. According to Bar et al., 2001, DOI: 10.1002/humu.5, variant c.1098+1G>T was identified in a male infant diagnosed with Type 5 Farber disease (Gene Reviews; https://www.ncbi.nlm.nih.gov/books/NBK488189/). The PCR product derived from the 3' portion of the acid cermidase (AC) cDNA (nucleotides 614 to 1236) was found to be smaller compared to the wild type control, indicating a deletion. Sequencing of the open reading frame revealed a deletion of nucleotides 1042 - 1098, which corresponds to exon 13 of the AC gene. This deletion of 19 amino acids (348 to 366) in the beta-subunit leads to a mutated and truncated protein, but no frameshift abnormality. Sequencing of the genomic DNA showed the underlying mutation responsible for the exon deletion was a transversion, G>T, of the first nucleotide in intron 13 (c.1098+1G>T). A second variant has not been identified on the alternate allele. Additionally, transfected COS-1 cells were utilyzed to measure acid ceramidase activity of the mutant protein. The mutant enzyme activity of cells expressing c.1098+1G>T was significantly less than control cells. |
| Invitae | RCV002549208 | SCV003440637 | pathogenic | not provided | 2022-09-26 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ASAH1 protein in which other variant(s) (p.Pro362Arg) have been determined to be pathogenic (PMID: 10610716, 23681708, 24164096, 29379059, 32449975). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 13, but is expected to preserve the integrity of the reading-frame (PMID: 11241842). ClinVar contains an entry for this variant (Variation ID: 812507). This variant is also known as IVS13+1G>T. Disruption of this splice site has been observed in individual(s) with clinical features of Farber lipogranulomatosis (PMID: 11241842). This variant is present in population databases (rs763842677, gnomAD 0.006%). This sequence change affects a donor splice site in intron 13 of the ASAH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. |