ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.835C>T (p.Arg279Ter) (rs121908645)

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Total submissions: 7
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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 criteria provided, single submitter clinical testing
Invitae RCV001376581 SCV001222396 pathogenic Citrullinemia 2020-07-30 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. This variant is present in population databases (rs121908645, ExAC 0.01%). This variant has been observed in several individuals affected with citrullinemia type 1 (PMID: 11571557, 27287393, 28111830, 16475226). ClinVar contains an entry for this variant (Variation ID: 6333). Loss-of-function variants in ASS1 are known to be pathogenic (PMID: 18473344, 19006241). 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.
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

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