Submissions for variant NM_054012.4(ASS1):c.835C>T (p.Arg279Ter)

gnomAD frequency: 0.00001  dbSNP: rs121908645

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000006705	SCV000220625	likely pathogenic	Citrullinemia type I	2014-08-22	criteria provided, single submitter	literature only
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000006705	SCV001156647	pathogenic	Citrullinemia type I	2019-08-29	criteria provided, single submitter	clinical testing	The ASS1 c.835C>T; p.Arg279Ter variant (rs121908645) has been described in the homozygous and compound heterozygous states in individuals diagnosed with citrullinemia (Gao 2003, Kleijer 2006, Li 2001). It is reported as pathogenic and likely pathogenic in ClinVar (Variation ID: 6333) and observed in the general population at a low overall frequency of 0.0024% (6/245706 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, RNA analysis of this variant in skin fibroblasts from an affected patient demonstrated an RNA-negative allele in which no stable mRNA was detected (Li 2001). Based on available information, this variant is considered pathogenic. References: Gao H et al. Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. Hum Mutat. 2003 Jul;22(1):24-34. Kleijer W et al. Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia. Prenat Diagn. 2006 Mar;26(3):242-7. Li C et al. A nonsense mutation is responsible for the RNA-negative phenotype in human citrullinaemia. Eur J Hum Genet. 2001 Sep;9(9):685-9.
Baylor Genetics	RCV000006705	SCV001163592	pathogenic	Citrullinemia type I	2024-03-09	criteria provided, single submitter	clinical testing
Invitae	RCV001376581	SCV001222396	pathogenic	Citrullinemia	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg279*) in the ASS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASS1 are known to be pathogenic (PMID: 18473344, 19006241). This variant is present in population databases (rs121908645, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with citrullinemia type 1 (PMID: 11571557, 16475226, 27287393, 28111830). ClinVar contains an entry for this variant (Variation ID: 6333). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000006705	SCV001338439	pathogenic	Citrullinemia type I	2020-04-30	criteria provided, single submitter	clinical testing	Variant summary: ASS1 c.835C>T (p.Arg279X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 250820 control chromosomes. c.835C>T has been reported in the literature in multiple individuals affected with Citrullinemia Type I (examples- Li_2001, Gao_2003, Kleijer_2006). These data indicate that the variant is very likely to be associated with disease. No stable mRNA was detected from the allele with the variant in RNA isolated from patient skin fibroblasts, presumably due to nonsense-mediated decay (Li_2001). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000006705	SCV002809909	pathogenic	Citrullinemia type I	2021-12-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000006705	SCV003814426	likely pathogenic	Citrullinemia type I	2021-12-21	criteria provided, single submitter	clinical testing
OMIM	RCV000006705	SCV000026896	pathogenic	Citrullinemia type I	2001-09-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000006705	SCV001453090	pathogenic	Citrullinemia type I	2020-09-16	no assertion criteria provided	clinical testing