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

dbSNP: rs121908638

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185782	SCV000238717	pathogenic	not provided	2023-01-18	criteria provided, single submitter	clinical testing	Published functional studies found this variant is associated with significantly decreased enzyme activity and thermal stability (Diez-Fernandez C et al., 2016); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18323623, 31469252, 27287393, 2358466)
Illumina Laboratory Services, 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	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 180 of the ASS1 protein (p.Ser180Asn). This variant is present in population databases (rs121908638, gnomAD 0.008%). This missense change has been observed in individual(s) with citrullinemia type I, including symptoms of hyperammonemia and markedly elevated plasma citrulline (PMID: 2358466, 18925679, 24765495; Invitae). ClinVar contains an entry for this variant (Variation ID: 6326). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ASS1 protein function with a positive predictive value of 80%. 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	2022-02-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000006698	SCV001163227	pathogenic	Citrullinemia type I		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000006698	SCV004238128	pathogenic	Citrullinemia type I	2023-06-20	criteria provided, single submitter	clinical testing
OMIM	RCV000006698	SCV000026889	pathogenic	Citrullinemia type I	2013-04-04	no assertion criteria provided	literature only