Submissions for variant NM_177924.5(ASAH1):c.125C>T (p.Thr42Met)

gnomAD frequency: 0.00004  dbSNP: rs145873635

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724837	SCV000331984	pathogenic	not provided	2015-07-30	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000029199	SCV000746510	likely pathogenic	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome	2017-12-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001270895	SCV001451676	pathogenic	ASAH1-related disorders	2019-02-12	criteria provided, single submitter	clinical testing	The ASAH1 c.173C>T (p.Thr58Met) variant is a missense variant that has been reported in four studies, in which it is found in a total of 10 individuals with spinal muscular atrophy associated with progressive myoclonic epilepsy, including in eight in a homozygous state and in two in a compound heterozygous state (Zhou et al. 2012; Rubboli et al. 2015; Giráldez et al. 2015; Yildiz et al. 2018). This variant segregated with disease in two families. The p.Thr58Met variant was absent from 95 control subjects but is reported at a frequency of 0.000196 in the African population of the Genome Aggregation Database. Transient expression of the p.Thr58Met cDNA into fibroblasts derived from an individual with Farber disease demonstrated that the acid-ceramidase activity was 32% of the wild type cDNA activity. Although there was no effect on the level of the precursor form or its processing, the α-subunit amount was mildly lower than the β-subunit amount (Zhou et al. 2012). Based on the collective evidence and application of the ACMG criteria, the p.Thr58Met variant is classified as pathogenic for ASAH1-related disorders.
Revvity Omics, Revvity	RCV000724837	SCV002019452	pathogenic	not provided	2019-09-06	criteria provided, single submitter	clinical testing
Invitae	RCV000724837	SCV002211845	pathogenic	not provided	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 42 of the ASAH1 protein (p.Thr42Met). This variant is present in population databases (rs145873635, gnomAD 0.02%). This missense change has been observed in individual(s) with with spinal muscular atrophy and progressive myoclonic epilepsy (PMID: 22703880, 25578555, 25847462, 27723502). 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: 35544). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000029199	SCV004100468	pathogenic	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome		criteria provided, single submitter	clinical testing	The missense variant p.T42M in ASAH1 (NM_177924.5) has been reported previously in affected patients (Zhou et al). Functional studies reveal a damaging effect. The p.T42M variant isobserved in 2/16,256 (0.0123%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between threonine and methionine. 3 variants within 6 amino acid positions of the variant p.T42M have been shown to be pathogenic, while none have been shown to be benign. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003390700	SCV004119531	likely pathogenic	ASAH1-related condition	2022-08-26	criteria provided, single submitter	clinical testing	The ASAH1 c.173C>T variant is predicted to result in the amino acid substitution p.Thr58Met. This variant (also known as c.125C>T, p.Thr42Met in transcript NM_177924.5) was reported in homozygous and compound heterozygous state in several individuals with Spinal muscular atrophy associated with progressive myoclonic epilepsy (Yildiz et al. 2017. PubMed ID: 29169047; Zhou et al. 2012. PubMed ID: 22703880; Akarsu et al. 2016. PubMed ID: 27723502; Giráldez et al. 2014. PubMed ID: 25578555; Rubboli et al. 2015. PubMed ID: 25847462). Functional expression studies of the c.173C>T mutant cDNA in Farber fibroblasts showed that acid-ceramidase activity was only 32% of that generated by normal cDNA, however this reduced activity was able to normalize the ceramide level in Farber cells. Knockdown of the ASAH1 ortholog in zebrafish led to a marked loss of motor-neuron axonal branching, a loss that is associated with increased apoptosis in the spinal cord and authors assume this could be the pathogenic mechanism underlying the CNS involvement in deficient cells in case of enzyme activity reduction in this variant (Zhou et al. 2012. PubMed ID: 22703880). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-17933050-G-A). This variant is interpreted as likely pathogenic.
OMIM	RCV000029199	SCV000051844	pathogenic	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome	2012-07-13	no assertion criteria provided	literature only
GeneReviews	RCV000029199	SCV000778526	not provided	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome		no assertion provided	literature only