Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001973772 | SCV002259795 | likely pathogenic | Hyperammonemia, type III | 2024-03-21 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 509 of the NAGS protein (p.Arg509Gln). This variant is present in population databases (rs759076608, gnomAD 0.004%). This missense change has been observed in individual(s) with N-acetylglutamate synthase deficiency (PMID: 15050968). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1474975). 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 not expected to disrupt NAGS protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects NAGS function (PMID: 15714518). 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. |
| Ambry Genetics | RCV002573419 | SCV003752547 | uncertain significance | Inborn genetic diseases | 2022-09-09 | criteria provided, single submitter | clinical testing | The c.1526G>A (p.R509Q) alteration is located in exon 7 (coding exon 7) of the NAGS gene. This alteration results from a G to A substitution at nucleotide position 1526, causing the arginine (R) at amino acid position 509 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.002% (5/282904) total alleles studied. The highest observed frequency was 0.004% (1/24972) of African alleles. This variant has been reported in trans with a NAGS pathogenic variant in individuals with clinical features of N-acetylglutamate synthase deficiency (Morizono, 2004; Caldovic, 2005; Caldovic, 2007). This amino acid position is highly conserved in available vertebrate species. Functional assays show that p.R509Q has reduced enzyme activity compared to the control in vitro (Caldovic, 2005). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Gene |
RCV003442983 | SCV004170691 | uncertain significance | not provided | 2023-05-01 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with a urea cycle disorder in the literature, but it is unknown whether this individual was tested for variants in other genes associated with urea cycle disorders (Caldovic et al., 2005); This variant is associated with the following publications: (PMID: 17421020, 15050968, 27037498, 15714518) |
| Baylor Genetics | RCV001973772 | SCV004199452 | likely pathogenic | Hyperammonemia, type III | 2024-02-05 | criteria provided, single submitter | clinical testing | |
| Genetics and Genomic Medicine Centre, |
RCV001973772 | SCV005873661 | pathogenic | Hyperammonemia, type III | 2020-09-02 | criteria provided, single submitter | clinical testing |