Submissions for variant NM_054012.4(ASS1):c.1173C>A (p.Phe391Leu)

gnomAD frequency: 0.00001  dbSNP: rs1554725724

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497925	SCV000589715	likely pathogenic	not provided	2016-01-07	criteria provided, single submitter	clinical testing	The F391L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The F391L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar 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 (T389I, G390R, and I394N) 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.
Invitae	RCV002230974	SCV001225237	uncertain significance	Citrullinemia	2022-04-06	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 391 of the ASS1 protein (p.Phe391Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of citrullinemia type I (PMID: 3146925; Invitae). ClinVar contains an entry for this variant (Variation ID: 432044). 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"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282180	SCV002572470	uncertain significance	not specified	2022-08-04	criteria provided, single submitter	clinical testing	Variant summary: ASS1 c.1173C>A (p.Phe391Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250698 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1173C>A has been reported in the literature in at least one individual with the biallelic genotype c.991T>C/c.1173C>A and diagnosis for Citrullinemia Type I (Zielonka_2019). Using a novel biallelic mammalian expression system Zielonka_2019 reported a residual enzyme activity of ~80% for this variant combination. This report does not provide unequivocal conclusions about association of the variant with Citrullinemia Type I. To our knowledge, no variant specific experimental evidence reporting an impact on function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000984146	SCV001132124	uncertain significance	Citrullinemia type I	2019-01-24	no assertion criteria provided	clinical testing