Submissions for variant NM_177924.5(ASAH1):c.1042-2A>C

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003681456	SCV004423286	likely pathogenic	not provided	2023-05-15	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with ASAH1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 12 of the ASAH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ASAH1 are known to be pathogenic (PMID: 24164096, 24355074).
Genetics laboratory, Department of Obstetrics & Gynae, Institute of Kidney Diseases & Research Centre Dr. H.L. Trivedi Institute Of Transplantation Sciences	RCV004784169	SCV005393900	likely pathogenic	Farber lipogranulomatosis		no assertion criteria provided	clinical testing	The c.1042-2A>C variant is novel in gnomAD exomes and is novel in 1000 genomes. This variant mutates a splice-acceptor sequence, potentially resulting in exon skipping and the production of abnormal proteins. In silico tools predict the splice site to be disrupted and the site is conserved across species. For this reasons, this variant has been classified as Likely Pathogenic.