Submissions for variant NM_177924.5(ASAH1):c.456A>C (p.Lys152Asn) (rs200455852)

Total submissions: 5

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.
Invitae	RCV000853058	SCV001236568	pathogenic	not provided	2019-09-08	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with asparagine at codon 152 of the ASAH1 protein (p.Lys152Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs200455852, ExAC 0.02%). This variant has been observed in individuals with ASAH1-related conditions (PMID: 26526000, 24164096, 25847462, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 180643). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 24164096). 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.