ClinVar Miner

Submissions for variant NM_177924.5(ASAH1):c.457+4A>G

dbSNP: rs767864356
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Medical Affairs, Dicerna Pharmaceuticals RCV001003331 SCV001161416 likely pathogenic Farber lipogranulomatosis 2019-07-01 criteria provided, single submitter literature only Variant c.457+4A>G is likely pathogenic. The patient (proband) was diagnosed with Farber disease characteristic of Type 1 Farber disease described in Gene Reviews ( DNA sequencing revealed compound heterozygous variants, c.126-3941_382+1358del and c.457+4A>G, in the ASAH1 gene and biparental segregation was confirmed. Variant c.457+4A>G was further investigated by Bashyam et al., 2014, using PCR and Sanger sequencing. This variant affects the 5' splice site in intron 6. The proband died at the age of 1 year. The mother requested genetic testing during a subsequent pregnancy using amniotic fluid analysis. ASAH1 variants were detected in a heterozygous state and genetic counseling was provided to the family accordingly. RT-PCR analyses on RNA isolated from fibroblasts generated from the amniotic fluid revealed a cDNA product of 140 bp (probably emanating from the mutant allele) in addition to the expected product of 215 bp (generated from the wildtype allele); the difference (75 bp) was equal to the size of exon 6. Determination of DNA sequence of the 140 bp cDNA product confirmed skipping of exon 6. DNA sequence analysis of the 215 bp product confirmed the wild-type sequence. Exon 6 is the region responsible for cleavage of enzyme precursor thus results in an ineffective acid ceramidase enzyme.
GeneDx RCV001553355 SCV001774211 likely pathogenic not provided 2023-09-22 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); Functional studies indicate that the c.457+4 A>G variant leads to abnormal splicing and results in skipping of exon 6 (Bashyam et al., 2014); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 22565078, 24355074)
Revvity Omics, Revvity RCV001553355 SCV002024365 likely pathogenic not provided 2019-10-22 criteria provided, single submitter clinical testing
Invitae RCV001553355 SCV002284232 pathogenic not provided 2023-07-14 criteria provided, single submitter clinical testing This sequence change falls in intron 6 of the ASAH1 gene. It does not directly change the encoded amino acid sequence of the ASAH1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs767864356, gnomAD 0.003%). This variant has been observed in individual(s) with Farber lipogranulomatous disease (PMID: 24355074). ClinVar contains an entry for this variant (Variation ID: 812501). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 24355074). This variant disrupts a region of the ASAH1 protein in which other variant(s) (p.Lys152Asn) have been determined to be pathogenic (PMID: 24164096, 25847462, 26526000; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002549207 SCV003598043 pathogenic Inborn genetic diseases 2022-01-24 criteria provided, single submitter clinical testing The c.457+4A>G intronic alteration consists of a A to G substitution nucleotides after coding exon 6 in the ASAH1 gene. Based on data from gnomAD, the G allele has an overall frequency of <0.01% (1/243356) total alleles studied. The highest observed frequency was <0.01% (1/29878) of South Asian alleles. This mutation was identified in the homozygous state in a child with Farber disease; biparental inheritance was confirmed (Muranjan, 2012; Bashyam, 2014). Based on internal structural analysis, the predicted impact of c.457+4A>G, p.E129_G153del, is deleterious; p.E129_G153del is destabilizing to the local structure and disrupts a putative key residue in protein function (Gebai, 2018; Dementiev, 2019). RT-PCR of fibroblasts from amniotic fluid of a carrier fetus showed a product 75 base pairs shorter than wild type due to aberrant splicing (Bashyam, 2014). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.

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