Submissions for variant NM_054012.4(ASS1):c.774-2A>G

dbSNP: rs1588496214

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001004536	SCV001163588	pathogenic	Citrullinemia type I	2024-03-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377855	SCV001575293	likely pathogenic	Citrullinemia	2022-02-03	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 813462). This variant has not been reported in the literature in individuals affected with ASS1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 11 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).
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001377855	SCV004046151	pathogenic	Citrullinemia		criteria provided, single submitter	clinical testing	A heterozygous c.774-2A>G variant in the ASS1 gene was detected in this individual. This variant affects the canonical splice donor site of intron 11/15 and is therefore predicted to interfere with splicing and result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in patients with inborn error of metabolism (PMID: 32778825). Loss-of-function variation in ASS1 is an established mechanism of disease (PMID: 18473344, 19006241). The c.774-2A>G variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.774-2A>G variant is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003425879	SCV004117771	pathogenic	ASS1-related disorder	2022-12-08	criteria provided, single submitter	clinical testing	The ASS1 c.774-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in a study utilizing exome sequencing in newborn screening to identify inborn errors of metabolism (Supplementary Table 5, Adhikari et al. 2020. PubMed ID: 32778825). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare and is reported as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/813462/). Variants that disrupt the consensus splice acceptor site in ASS1 are expected to be pathogenic. This variant is interpreted as pathogenic.