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

gnomAD frequency: 0.00005  dbSNP: rs192838388

Total submissions: 14

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	likely pathogenic	Citrullinemia type I	2017-11-10	criteria provided, single submitter	clinical testing	The p.Val263Met (NM_000050.4 c.787G>A) variant in ASS1 has been reported in at l east 6 compound heterozygous and 6 homozygous individuals with mild citrullinemi a and segregated in 2 siblings from two families (Haeberle 2003 and Diez-Fernand ez 2017). Some of these individuals were asymptomatic despite having mild hyperc itrullinaemia (Haeberle 2003 and Diez-Fernandez 2017). This variant has also bee n reported in ClinVar (Variation ID#92372), as pathogenic. This variant led to r educed enzyme activity (36% as compared to wild-type) in in vitro studies (Berni ng 2008). It has been identified in 0.01% (1/10148) of Ashkenazi Jewish chromoso mes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org ; dbSNP rs192838388). Although this variant has been seen in the general populat ion, its frequency is low enough to be consistent with a recessive carrier frequ ency. In summary, although additional studies are required to fully establish it s clinical significance, the p.Val263Met variant is likely pathogenic for citr ullinemia in an autosomal recessive manner, though it is associated with a mild phenotype. ACMG/AMP Criteria applied: PM3 (upgraded to Strong based on multiple occurrences), PM2, PP5.
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