Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000853547 | SCV000995946 | likely pathogenic | not provided | 2024-04-03 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect, resulting in loss of enzymatic activity (PMID: 10610716, 11241842); Reported in a patient with Farber disease in published literature; study did not specify specific clinical information or if a second variant in ASAH1 was identified (PMID: 10610716); Reported along with a second variant in the ASAH1 gene in multiple patients with Farber disease in the published literature; but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (PMID: 11241842, 30815900, 32449975, 34240417); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 11241842, 32449975, 30815900, 34240417, 10610716) |
| Labcorp Genetics |
RCV000853547 | SCV003440687 | likely pathogenic | not provided | 2023-09-08 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 138 of the ASAH1 protein (p.Glu138Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Farber lipogranulomatosis (PMID: 10610716, 11241842, 32449975, 34240417). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 92). 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. Experimental studies have shown that this missense change affects ASAH1 function (PMID: 10610716). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| OMIM | RCV000000112 | SCV000020255 | pathogenic | Farber lipogranulomatosis | 1999-12-01 | no assertion criteria provided | literature only |