ClinVar Miner

Submissions for variant NM_000050.4(ASS1):c.805G>A (p.Val269Met) (rs370595480)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000174211 SCV000800723 uncertain significance Citrullinemia type I 2017-04-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000412912 SCV000225474 uncertain significance not provided 2018-06-22 criteria provided, single submitter clinical testing
GeneDx RCV000412912 SCV000490413 pathogenic not provided 2015-05-07 criteria provided, single submitter clinical testing The V269M missense variant in the ASS1 gene has been reported previously in association with classic citrullinemia (Gao et al., 2003). It was hypothesized that the V269M variant may affect the tertiary and/or quaternary structure of the protein (Gao et al., 2003). Further, V269M occurs at a position that is conserved across mammals, in silico analysis predicts this variant is probably damaging to the protein structure/function, and missense variants in nearby residues (R265C, R265H, E270Q, R272C) have also been reported in the Human Gene Mutation Database in association with citrullinaemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret V269M to be pathogenic mutations.
Genetic Services Laboratory, University of Chicago RCV000174211 SCV000593462 likely pathogenic Citrullinemia type I 2017-04-13 criteria provided, single submitter clinical testing
Invitae RCV000174211 SCV000957991 uncertain significance Citrullinemia type I 2018-09-07 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 269 of the ASS1 protein (p.Val269Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs370595480, ExAC 0.01%). This variant has been observed on the opposite chromosome (in trans) from a variant in an individual affected with mild citrullinemia type 1 (PMID: 12815590) and has been reported in other unrelated mildly affected individuals (PMID: 14680976, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 193968). 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.

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