Submissions for variant NM_177924.5(ASAH1):c.456A>C (p.Lys152Asn)

gnomAD frequency: 0.00004  dbSNP: rs200455852

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000853058	SCV000994982	likely pathogenic	not provided	2019-05-28	criteria provided, single submitter	clinical testing	The c.456 A>C variant in the ASAH1 gene has been reported previously, as K152N and K168N, in a few unrelated individuals with spinal muscular atrophy with progressive myoclonic epilepsy who also harbored a second ASAH1 variant (Dyment et al., 2014; Gan et al., 2015; Kernohan et al., 2017). Functional studies of cultured patient-derived fibroblasts demonstrate reduction in both acid ceramidase levels and enzymatic activity (Dymet et al., 2014). The c.456 A>C variant is observed in 5/34116 alleles (0.0147%) from individuals of Latino background in large population cohorts, with no homozygotes observed (Lek et al., 2016). In-silico splice models predict that c.456 A>C may destroy the natural splice donor site of intron 6. However, in the absence of RNA/functional studies, the actual effect of the c.456 A>C change in this individual is unknown. If c.456 A>C does not alter splicing, it will result in the K152N missense change. The K152N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret c.456 A>C as a likely pathogenic variant.
Medical Affairs, Dicerna Pharmaceuticals	RCV000157605	SCV001161424	pathogenic	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome	2019-07-01	criteria provided, single submitter	literature only	Although variant c.456A>C has been noted in Clinvar as a variant with conflicting evidence, there is significant new evidence that supports the clinical pathogenicity of c.456A>C. In addition to the patient described by Gan et al., 2015, DOI: 10.1016/j.nmd.2015.09.007, this variant has been described in 4 additional patients from unrelated families and published in Cozma et al., 2017, DOI:10.1038/s41598-017-06604-2, Dyment et al., 2014, doi: 10.1111/cge.12307, Kernohan et al., 2017, doi:10.1002/humu.23211, and Rubboli et al., 2017, doi: 10.1111/epi.12977. In the patient described in Gan et al., 2015, histological studies were completed demonstrating the presence of zebra bodies that are characteristic of acid ceramidase deficiency. Additionally, functional studies have been conducted using this variant. Acid ceramidase enzyme activity was measured in this patient's and mother's fibroblasts. The patient has approximately 15% enzyme activity of controls and the mother has acid ceramidase activity of approximately 50% normal.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000853058	SCV001236568	pathogenic	not provided	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 152 of the ASAH1 protein (p.Lys152Asn). This variant is present in population databases (rs200455852, gnomAD 0.01%). This missense change has been observed in individual(s) with ASAH1-related conditions (PMID: 24164096, 25847462, 26526000; 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: 180643). 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 tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000157605	SCV000207414	pathogenic	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome	2014-12-01	no assertion criteria provided	literature only
Care4Rare-SOLVE, CHEO	RCV000157605	SCV000494575	uncertain significance	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome	2017-01-01	no assertion criteria provided	research	This variant was found in a compound heterozygous state NM_004315.4:c.458A>G.
PreventionGenetics, part of Exact Sciences	RCV004551355	SCV004720033	likely pathogenic	ASAH1-related disorders	2024-03-01	no assertion criteria provided	clinical testing	The ASAH1 c.504A>C variant is predicted to result in the amino acid substitution p.Lys168Asn. This variant (also known as c.456A>C; p.Lys152Asn) was reported in compound heterozygous state in multiple individuals with spinal muscular atrophy associated with progressive myoclonic epilepsy (Dyment et al. 2014. PubMed ID: 24164096; Gan et al. 2015. PubMed ID: 26526000; Cozma et al. 2017. PubMed ID: 28733637; Kernohan et al. 2017. PubMed ID: 28251733; Rubboli et al. 2015. PubMed ID: 25847462). In a patient who was compound heterozygous for this variant and p.Gly284X, functional studies in cultured fibroblasts showed significantly reduced acid ceramidase enzymatic activity (Dyment et al. 2014. Pubmed ID: 24164096). Experimental studies have shown that this variant disrupts mRNA splicing (Kernohan et al. 2017. Pubmed ID: 28251733). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.