ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.919C>T (p.Arg307Cys) (rs183276875)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255358 SCV000321410 likely pathogenic not provided 2017-10-23 criteria provided, single submitter clinical testing The R307C variant has has been reported previously in an asymptomatic patient with very mild citrullinemia who was diagnosed after a positive newborn screening result and in whom a second variant in the ASS1 gene was identified; however, whether or not the two variants were present on the same (in cis) or opposite (in trans) ASS1 allele was not reported (Haberle et al., 2003). The R307C variant has also been reported in a patient who had a positive newborn screening result in whom a second variant in ASS1 was not identified (Martín-Hernández et al. 2014). The R307C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R307C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other 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. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV001376643 SCV000630066 pathogenic Citrullinemia 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 307 of the ASS1 protein (p.Arg307Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs183276875, ExAC 0.02%). This variant has been reported in combination with another ASS1 variant in individuals affected with citrullinemia (PMID: 14680976, Invitae) and it has been observed to segregate with citrullinemia in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 265044). 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: Benign; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000558661 SCV001163595 pathogenic Citrullinemia type I criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000558661 SCV001653431 likely pathogenic Citrullinemia type I 2021-05-18 criteria provided, single submitter clinical testing

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