ClinVar Miner

Submissions for variant NM_177924.5(ASAH1):c.410A>G (p.Tyr137Cys) (rs371666412)

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Total submissions: 2
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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.
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.

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