ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.689-2A>C

gnomAD frequency: 0.00001  dbSNP: rs374586230
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV001004534 SCV001163585 pathogenic Citrullinemia type I criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002509589 SCV002819833 likely pathogenic Citrullinemia 2022-12-27 criteria provided, single submitter clinical testing Variant summary: ASS1 c.689-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251336 control chromosomes. To our knowledge, no occurrence of c.689-2A>C in individuals affected with Citrullinemia Type I and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV002509589 SCV003471351 likely pathogenic Citrullinemia 2023-10-22 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 10 of the ASS1 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 ASS1 are known to be pathogenic (PMID: 18473344, 19006241). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with ASS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 813460). 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.

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