Submissions for variant NM_177924.5(ASAH1):c.994G>C (p.Asp332His)

dbSNP: rs941670381

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414472	SCV000492143	likely pathogenic	not provided	2016-12-14	criteria provided, single submitter	clinical testing	The D332H variant in the ASAH1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D332H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D332H 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. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. As an alternate mechanism, multiple in silico algorithms predict that c.994 G>C (aka D332H) might create or enhance a cryptic acceptor site in exon 12. However, in the absence of RNA/functional studies, the actual effect of c.994 G>C in this individual is unknown. Missense variants in nearby residues (D331N, R333G, R333H) have been reported in the Human Gene Mutation Database in association with Farber disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. The D332H variant is a strong candidate for a pathogenic variant
Revvity Omics, Revvity	RCV000414472	SCV003825066	uncertain significance	not provided	2019-06-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000414472	SCV005830729	likely pathogenic	not provided	2024-09-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 332 of the ASAH1 protein (p.Asp332His). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with Farber disease (PMID: 32449975; internal data). 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: 373542). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ASAH1 protein function with a negative predictive value of 80%. 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.