ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.847G>A (p.Glu283Lys) (rs765338121)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493705 SCV000582868 likely pathogenic not provided 2015-12-03 criteria provided, single submitter clinical testing The E283K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R279Q, G280R, T284I) have been reported in the Human Gene Mutation Database in association with citrullinemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Counsyl RCV000672066 SCV000797126 likely pathogenic Citrullinemia type I 2018-01-12 criteria provided, single submitter clinical testing
Invitae RCV001290024 SCV001400981 pathogenic Citrullinemia 2020-08-05 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 283 of the ASS1 protein (p.Glu283Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs765338121, ExAC 0.006%). This variant has been observed to be homozygous or in combination with another ASS1 variant in individuals affected with citrullinemia type I (PMID: 12815590, 16475226, 23611581, 28111830, Invitae). ClinVar contains an entry for this variant (Variation ID: 430139). 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: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000672066 SCV001471500 likely pathogenic Citrullinemia type I 2020-01-02 criteria provided, single submitter clinical testing The ASS1 c.847G>A; p.Glu283Lys variant (rs765338121) is reported in the literature in the homozygous or compound heterozygous state in several individuals affected with citrullinemia (Diez-Fernandez 2017, Gao 2003, Kleijer 2006). This variant is reported in ClinVar (Variation ID: 430139), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamic acid at codon 283 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Diez-Fernandez C et al. Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations. Hum Mutat. 2017 May;38(5):471-484. Gao HZ 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 WJ 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.
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000672066 SCV000863819 likely pathogenic Citrullinemia type I 2018-02-19 no assertion criteria provided clinical testing

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