ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.1168G>A (p.Gly390Arg) (rs121908641)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000185789 SCV000109857 pathogenic not provided 2018-04-20 criteria provided, single submitter clinical testing
GeneDx RCV000185789 SCV000238725 pathogenic not provided 2017-10-20 criteria provided, single submitter clinical testing The G390R variant in the ASS1 gene has been reported previously in association with classic citrullinemia (Kobayashi et al., 1990; Diez-Fernandez et al., 2016). Functional analysis of G390R found it is associated with less than 2% of wild type argininosuccinate synthetase activity (Berning et al., 2008). Therefore, we interpret G390R to be a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000006701 SCV000611160 pathogenic Citrullinemia type I 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000006701 SCV000630052 pathogenic Citrullinemia type I 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 390 of the ASS1 protein (p.Gly390Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs121908641, ExAC 0.1%). This variant is a known common cause of citrullinemia type I. It has been reported worldwide in multiple affected individuals and families with evidence of disease co-segregation (PMID: 23430935, 11708871, 19358837, 12815590, 18473344, 19006241). ClinVar contains an entry for this variant (Variation ID: 6329). Experimental studies have shown that this variant disrupts the function and substantially reduces the activity of the encoded enzyme in vitro (PMID: 18473344, 8792870). For these reasons, this variant has been classified as Pathogenic.
Myriad Women's Health, Inc. RCV000006701 SCV000677973 likely pathogenic Citrullinemia type I 2015-09-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000006701 SCV000694161 pathogenic Citrullinemia type I 2016-04-12 criteria provided, single submitter clinical testing Variant summary: The ASS1 c.1168G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Arg. Gly390 is located in a-helix 12 and is important for intermolecular contact of the multimerization tails, and 5/5 in-silico tools predict damaging outcome for this variant. The enzymatic ASS activity of G390R was shown to be below 2% of the wild-type protein (Berning_HM_2008). This variant was found in 45/113324 control chromosomes at a frequency of 0.0003971, which does not exceed maximal expected frequency of a pathogenic ASS1 allele (0.0040825). This variant is reported as the most common mutation in patients with the classic phenotype of citrullinemia. In addition, several clinical laboratories classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Baylor Genetics RCV000006701 SCV001163604 pathogenic Citrullinemia type I criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000006701 SCV001193921 likely pathogenic Citrullinemia type I 2019-11-12 criteria provided, single submitter clinical testing NM_000050.4(ASS1):c.1168G>A(G390R) is classified as likely pathogenic in the context of citrullinemia type 1. Sources cited for classification include the following: PMID 18473344, 16475226, 12815590, and 7557970. Classification of NM_000050.4(ASS1):c.1168G>A(G390R) is based on the following criteria: There is strong evidence of association with the variant and the relevant disease and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000185789 SCV001248850 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
OMIM RCV000006701 SCV000026892 pathogenic Citrullinemia type I 2009-03-01 no assertion criteria provided literature only
GeneReviews RCV000006701 SCV000323098 pathogenic Citrullinemia type I 2016-09-01 no assertion criteria provided literature only
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000006701 SCV000787654 likely pathogenic Citrullinemia type I 2016-08-29 no assertion criteria provided clinical testing The observed variant c.1168G>A (p.Gly390Arg) is not reported in 1000 Genomes and has a minor allele frequency of 0.00040 in ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT and probably damaging by Polyphen2.

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