ClinVar Miner

Submissions for variant NM_153006.3(NAGS):c.872T>A (p.Ile291Asn)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Revvity Omics, Revvity RCV003142548 SCV003808558 likely pathogenic Hyperammonemia, type III 2022-05-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV003142548 SCV003835017 uncertain significance Hyperammonemia, type III 2021-12-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004701010 SCV005203499 uncertain significance not specified 2024-07-16 criteria provided, single submitter clinical testing Variant summary: NAGS c.872T>A (p.Ile291Asn) results in a non-conservative amino acid change located in the Aspartate/glutamate/uridylate kinase domain (IPR001048) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247922 control chromosomes. c.872T>A has been reported in the homozygous state in multiple related individuals in the literature affected with clinical features NAGS deficiency (example, Sancho-Vaello_2016), however the clinical course was late-onset/mild, and follow up assessments described phenotypes as "normal" and not requiring N-carbamyl-L-glutamate therapy. These data indicate that the variant may be associated with a mild, hypomorphic, and/or partial presentation of disease which may be influenced by environmental factors. Multiple publications report experimental in vitro evidence evaluating an impact on protein function in both bacterial and human-derived models of the enzyme encoded by NAGS. The most pronounced variant effect results in 30%-50% of normal enzyme activity, and thermal instability has also been noted (example, Sancho-Vaello_2016, Gougeard_2024). The following publications have been ascertained in the context of this evaluation (PMID: 27570737, 27037498, 38740568). ClinVar contains an entry for this variant (Variation ID: 2432020). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.