Submissions for variant NM_177924.5(ASAH1):c.410A>G (p.Tyr137Cys)

gnomAD frequency: 0.00001  dbSNP: rs371666412

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Medical Affairs, Dicerna Pharmaceuticals	RCV000416939	SCV001161388	pathogenic	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome	2019-06-19	criteria provided, single submitter	literature only	Based on new evidence the previous Clinvar classification of VUS can be revised to clinically pathogenic for variant c.410A>G. There have been 2 patients diagnosed with SMA-PME from 2 unrelated families who have carried the variant c.410A>G. The patient decribed in Kernohan et al., 2017, doi:10.1002/humu.23211, had compound heterozygous variants in the ASAH1 gene. The variant in ASAH1 (c.410A>G; p.Tyr153Cys) was reported and classified as a variant of unknown significance, but was highly suspicious based on its rarity in control cohorts (seen in one of 70,372 alleles in ExAC Browser), and it is predicted to be deleterious to protein function (PolyPhen-2 [1.0], SIFT [0.0]). Additional functional testing in this patient was conducted by quantifying cellular ceramide content using high-performance liquid chromatography electrospray ionization tandem mass spectrometry in extracts from patient and control fibroblast cells. Eighteen distinct ceramide species with a d18:1 sphingosine backbone were detected; a significant increase was observed in 17 of the 18 ceramides, confirming the loss of acid ceramidase function, and thus the pathogenicity of the ASAH1 variants. Additionally, a second patient diagnosed with SMA-PME from an unrelated family has been described in Cozma et al., 2018, DOI:10.1038/s41598-017-06604-2 further substantiating this variant as clinically pathogenic.
Invitae	RCV001861470	SCV002302145	likely pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	This variant disrupts the p.Tyr137 amino acid residue in ASAH1. Other variant(s) that disrupt this residue have been observed in individuals with ASAH1-related conditions (PMID: 32449975), which suggests that this may be a clinically significant amino acid residue. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 137 of the ASAH1 protein (p.Tyr137Cys). This variant is present in population databases (rs371666412, gnomAD 0.005%). This missense change has been observed in individual(s) with Farber disease or spinal muscular atrophy (PMID: 28251733, 32449975). ClinVar contains an entry for this variant (Variation ID: 375548). 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. 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.
Fulgent Genetics, Fulgent Genetics	RCV002502451	SCV002810273	likely pathogenic	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome; Farber lipogranulomatosis	2022-02-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003418103	SCV004114000	likely pathogenic	ASAH1-related condition	2022-08-29	criteria provided, single submitter	clinical testing	The ASAH1 c.458A>G variant is predicted to result in the amino acid substitution p.Tyr153Cys. This variant (also known as c.410A>G; p.Tyr137Cys) has been reported in the homozygous state in at least four individuals with Farber disease (Table1, Cozma et al. 2017. Pubmed ID: 28733637; Internal Data, PreventionGenetics). It has also been reported in the compound heterozygous state in at least two individuals, one of whom had spinal muscular atrophy with progressive myoclonic epilepsy and the other for whom there was clinical suspicion of Farber disease (Kernohan et al. 2017. Pubmed ID: 28251733; Internal Data, PreventionGenetics). Internal data suggests this variant is enriched in individuals of French-Canadian ancestry (Internal Data, PreventionGenetics). Biochemical studies using patient-derived fibroblasts indicate this variant results in loss of ASAH1 function (Figure 2, Kernohan et al. 2017. Pubmed ID: 28251733). This variant is reported in 0.0050% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-17922013-T-C). This variant is interpreted as likely pathogenic.
Care4Rare-SOLVE, CHEO	RCV000416939	SCV000494574	uncertain significance	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome	2017-01-01	no assertion criteria provided	clinical testing	This variant was found in a compound heterozygous state with NM_004315.4:c.504A>C.