ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.539G>A (p.Ser180Asn) (rs121908638)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185782 SCV000238717 pathogenic not provided 2016-03-29 criteria provided, single submitter clinical testing The S180N mutation in the ASS1 gene has been reported previously in a single patient with neonatal citrullinemia who was compound heterozygous for another missense mutation (Kobayashi et al., 1990). This mutation is a conservative substitution of one neutral and polar amino acid for another at a residue that is conserved across species. In silico analysis predicts this mutation is probably damaging to the protein structure/function. The S180N mutation was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret S180N as a disease-causing mutation.
Illumina Clinical Services Laboratory,Illumina RCV000006698 SCV000477626 likely pathogenic Citrullinemia type I 2017-04-28 criteria provided, single submitter clinical testing The ASS1 c.539G>A (p.Ser180Asn) variant has been reported in a total of three individuals with citrullinemia, all in a compound heterozygous state (Kobayashi et al. 1990; Dimmock et al. 2008; Rhee et al. 2013). Control data are not available for this variant, which is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium, though this is based on one allele in a region of good sequencing coverage. Functional studies in E. coli demonstrated the p.Ser180Asn variant had decreased binding affinity for aspartate and citrulline. The activity of the p.Ser180Asn variant increased to approximately 10% of wild type when exposed to large doses of aspartate (Diez-Fernandez et al. 2016). Based on the evidence, the p.Ser180Asn variant is classified as likely pathogenic for citrullinemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001376618 SCV000630060 pathogenic Citrullinemia 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 180 of the ASS1 protein (p.Ser180Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs121908638, ExAC 0.001%). This variant has been reported in individuals affected with citrullinemia type I, including symptoms of hyperammonemia and markedly elevated plasma citrulline (PMID: 2358466, 24765495, 18925679, Invitae). ClinVar contains an entry for this variant (Variation ID: 6326). A previous study has shown that argininosuccinate synthetase activity is not detectable in patient fibroblasts (PMID: 2358466). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000006698 SCV000694165 pathogenic Citrullinemia type I 2017-03-10 criteria provided, single submitter clinical testing Variant summary: The ASS1 c.539G>A (p.Ser180Asn) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/121356 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASS1 variant (0.0040825). The variant has been reported in affected individuals in the literature, and was shown in experimental studies to result in ~10% enzyme activity (Diez-Fernandez_2016). Additionally, an internal specimen carrying this variant was specified to have affected cousin who was homozygous for the mutation. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
SIB Swiss Institute of Bioinformatics RCV000006698 SCV000803612 likely pathogenic Citrullinemia type I 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Citrullinemia 1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3 => Well-established functional studies show a deleterious effect (PMID:27287393).
Fulgent Genetics,Fulgent Genetics RCV000006698 SCV000893797 pathogenic Citrullinemia type I 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000006698 SCV001163227 pathogenic Citrullinemia type I criteria provided, single submitter clinical testing
OMIM RCV000006698 SCV000026889 pathogenic Citrullinemia type I 2013-04-04 no assertion criteria provided literature only

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.