Submissions for variant NM_001875.5(CPS1):c.3521G>A (p.Arg1174Gln)

gnomAD frequency: 0.00001  dbSNP: rs553145464

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001143011	SCV001303507	uncertain significance	Congenital hyperammonemia, type I	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001143011	SCV001421240	uncertain significance	Congenital hyperammonemia, type I	2021-08-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 1174 of the CPS1 protein (p.Arg1174Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs553145464, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with CPS1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV003353173	SCV004077018	uncertain significance	Inborn genetic diseases	2023-07-05	criteria provided, single submitter	clinical testing	The c.3521G>A (p.R1174Q) alteration is located in exon 29 (coding exon 29) of the CPS1 gene. This alteration results from a G to A substitution at nucleotide position 3521, causing the arginine (R) at amino acid position 1174 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001143011	SCV002076262	uncertain significance	Congenital hyperammonemia, type I	2020-03-20	no assertion criteria provided	clinical testing