Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Medical Affairs, |
RCV001003320 | SCV001161404 | likely pathogenic | Farber lipogranulomatosis | 2019-06-19 | criteria provided, single submitter | literature only | Variant c.997C>T is likely pathogenic based on the following rationale. Variant c.997C>T has been identified in 2 patients diagnosed with Farber disease from unrelated families. Kim et al., 2016, DOI: 10.1002/ajmg.a.37846 is an infant with characteristic clinical features of Type 1 Farber disease (Gene Reviews; https://www.ncbi.nlm.nih.gov/books/NBK488189/). Whole exome sequencing was conducted and compound heterozygous variants were identified in the ASAH1 gene, c.703G>C and c.997C>T. When analyzed using public databases (dbSNP build 137; 1000 Genomes Project release 10.31.2012; NHLBI Exome Sequencing Project), variants were determined to be rare with pathogenic consequences according to Polyphen and SIFT analyses. Variant c.997C>T has also been identified in a second Farber disease patient described in Cozma et al., 2017, DOI:10.1038/s41598-017-06604-2. The patient was a newborn with homozygous c.997C>T variants in the ASAH1 gene. Additional ceramide biomarker testing was completed in this patient along with 2 additional newborn patients diagnosed with Farber disease demonstrating C26:0 levels were significantly higher in this cohort compared to controls. |
Invitae | RCV001860534 | SCV002112335 | likely pathogenic | not provided | 2022-12-06 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 812490). This variant is also known as c.1045C>T(p.Arg349Cys). This missense change has been observed in individuals with Farber disease (PMID: 27411168, 28733637). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 333 of the ASAH1 protein (p.Arg333Cys). This variant disrupts the p.Arg333 amino acid residue in ASAH1. Other variant(s) that disrupt this residue have been observed in individuals with ASAH1-related conditions (PMID: 24355074, 28733637), which suggests that this may be a clinically significant amino acid residue. 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. |