ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.787G>A (p.Val263Met)

gnomAD frequency: 0.00005  dbSNP: rs192838388
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000185783 SCV000109862 pathogenic not provided 2012-12-03 criteria provided, single submitter clinical testing
GeneDx RCV000185783 SCV000238719 pathogenic not provided 2020-05-05 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect, V263M mutant protein expressed in E.coli yielded 30% residual enzymatic activity (Berning et al., 2008); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23757202, 21244552, 18925679, 18473344, 14680976, 20690080, 26589311, 28111830, 30609409, 31469252)
Fulgent Genetics, Fulgent Genetics RCV000078024 SCV000611161 pathogenic Citrullinemia type I 2021-11-10 criteria provided, single submitter clinical testing
Counsyl RCV000078024 SCV000678048 likely pathogenic Citrullinemia type I 2017-06-16 criteria provided, single submitter clinical testing V263M may be associated with a mild form of citrullinemia type 1.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000078024 SCV000732017 pathogenic Citrullinemia type I 2023-02-21 criteria provided, single submitter clinical testing The p.Val263Met (NM_000050.4 c.787G>A) variant in ASS1 has been reported in at least 6 compound heterozygous and 6 homozygous individuals with mild citrullinemia and segregated in 2 siblings from two families (Haeberle 2003 PMID: 14680976, Diez-Fernandez 2017 PMID: 28111830). Some of these individuals were asymptomatic despite having mild hypercitrullinaemia (Haeberle 2003 PMID: 14680976, Diez-Fernandez 2017 PMID: 28111830). It has been identified in 0.01% (1/10148) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs192838388), and ] has also been reported in ClinVar (Variation ID#92372) as pathogenic by several clinical laboratories. This variant led to reduced enzyme activity (36% as compared to wild-type) in in vitro studies (Berning 2008 PMID: 18473344). In addition, computational prediction tools suggest that the variant may impact the protein. In summary, the p.Val263Met variant meets criteria to be classified as pathogenic for citrullinemia in an autosomal recessive manner, though it is associated with a milder phenotype. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Moderate, PS3_Supporting, PM2_Supporting, PP3.
Invitae RCV001376591 SCV000754759 pathogenic Citrullinemia 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 263 of the ASS1 protein (p.Val263Met). This variant is present in population databases (rs192838388, gnomAD 0.01%). This missense change has been observed in individuals with Citrullinemia type I (PMID: 4680976, 18473344, 18925679, 23780642). ClinVar contains an entry for this variant (Variation ID: 92372). 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 expected to disrupt ASS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ASS1 function (PMID: 18473344). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000078024 SCV001163589 pathogenic Citrullinemia type I criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000078024 SCV001338490 pathogenic Citrullinemia type I 2020-04-02 criteria provided, single submitter clinical testing Variant summary: ASS1 c.787G>A (p.Val263Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251362 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ASS1 causing Citrullinemia Type I (4.8e-05 vs 0.0041), allowing no conclusion about variant significance. c.787G>A has been reported in the literature in multiple individuals in compound heterozygous or homozygous state affected with mild citrullinemia (Haberie_2003, Dimmock_2008, Barends_2014, Diez-Fernandez_2017). These data indicate that the variant is very likely to be associated with disease. At least one in vitro functional study reports this variant had an impact on protein function and results in 36% of normal activity. Six Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (4x) and likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000078024 SCV001448988 pathogenic Citrullinemia type I 2019-09-09 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000185783 SCV001962577 pathogenic not provided 2021-09-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000078024 SCV002019921 pathogenic Citrullinemia type I 2022-12-13 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000078024 SCV002768507 pathogenic Citrullinemia type I 2019-08-28 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_000050.4(ASS1):c.787G>A, has been identified in exon 12 of 16 of the ASS1 gene. The variant is predicted to result in a minor amino acid change from valine to methionine at position 263 of the protein (NP_000041.2(ASS1):p.(Val263Met)). The valine residue at this position has high conservation (100 vertebrates, UCSC), and is located within the Arginosuccinate synthase domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.005% (15 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic and segregated with disease in multiple families with citrullinemia (ClinVar, Häberle, J. et al. (2003), Berning, C. et al. (2008), Glamuzina, E. et al. (2011), Diez-Fernandez, C. et al. (2017)). Additionally, in vitro studies demonstrated a reduced enzyme activity in p.V263M (Berning, C. et al. (2008)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
GeneReviews RCV000078024 SCV000323089 not provided Citrullinemia type I no assertion provided literature only
Natera, Inc. RCV000078024 SCV002085092 pathogenic Citrullinemia type I 2020-06-01 no assertion criteria provided clinical testing

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