Submissions for variant NM_177924.5(ASAH1):c.1079C>T (p.Thr360Ile)

gnomAD frequency: 0.00001  dbSNP: rs371520705

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001163942	SCV001326032	uncertain significance	Farber lipogranulomatosis	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859052	SCV002118628	uncertain significance	not provided	2022-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 360 of the ASAH1 protein (p.Thr360Ile). This variant is present in population databases (rs371520705, gnomAD 0.008%). This missense change has been observed in individual(s) with ASAH1-related conditions and/or clinical features of ASAH1-related conditions (PMID: 32627310). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as NM_004315.6:c.1127C>T p.Thr376Ile. ClinVar contains an entry for this variant (Variation ID: 911468). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant disrupts the p.Thr360 amino acid residue in ASAH1. Other variant(s) that disrupt this residue have been observed in individuals with ASAH1-related conditions (PMID: 32875576), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001859052	SCV003805081	uncertain significance	not provided	2022-08-19	criteria provided, single submitter	clinical testing	Observed with a second variant on the opposite allele (in trans) in a patient with clinical features of both Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy in the published literature (Lee et al., 2020); 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; This variant is associated with the following publications: (PMID: 32627310)
Revvity Omics, Revvity	RCV001859052	SCV004234514	uncertain significance	not provided	2023-06-14	criteria provided, single submitter	clinical testing