ClinVar Miner

Submissions for variant NM_177924.5(ASAH1):c.991G>A (p.Asp331Asn)

dbSNP: rs1354060089
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Medical Affairs, Dicerna Pharmaceuticals RCV001003325 SCV001161409 uncertain significance Farber lipogranulomatosis 2019-06-19 criteria provided, single submitter literature only Variant c.991G>A has been determined to have uncertain clinical significance. The patient is described in Bar et al., 2001, DOI: 10.1002/humu.5, as an infant with Type 3 or mild Farber disease (Gene Reviews; https://www.ncbi.nlm.nih.gov/books/NBK488189/). The variant was identified through cDNA sequencing and was confirmed at the genomic level. Additionally, the variant was inherited from the healthy carrier mother. There is no functional testing of c.991G>A to further determine its pathogenicity. Although this variant has been given uncertain significance, a high degree of clinical suspicion should be used to assess patients who carry this variant for Farber disease symptoms.
Labcorp Genetics (formerly Invitae), Labcorp RCV003558632 SCV004294549 likely pathogenic not provided 2023-05-31 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change affects ASAH1 function (PMID: 11241842). 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: 812495). This missense change has been observed in individual(s) with Farber disease (PMID: 11241842). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 331 of the ASAH1 protein (p.Asp331Asn).

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