ClinVar Miner

Submissions for variant NM_000050.4(ASS1):c.262C>A (p.Leu88Ile) (rs895822620)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000527150 SCV000800422 uncertain significance Citrullinemia type I 2018-06-05 criteria provided, single submitter clinical testing
GeneDx RCV000489131 SCV000577166 uncertain significance not provided 2017-04-07 criteria provided, single submitter clinical testing The L88I missense variant in the ASS1 gene has been previously reported in a homozygous state intwo asymptomatic individuals with abnormal newborn screening and elevated citrulline (Dimmock etal., 2008; Barends et al., 2014). The L88I variant is not observed in large population cohorts (Lek etal., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L88I variant is aconservative amino acid substitution, which is not likely to impact secondary protein structure asthese residues share similar properties. This substitution occurs at a position that is conserved acrossspecies. In silico analysis is inconsistent in its predictions as to whether or not the variant is damagingto the protein structure/function. Therefore, based on the currentlyavailable information, it is unclear whether this variant is a pathogenic variant or a rare benignvariant.
Invitae RCV000527150 SCV000630055 likely pathogenic Citrullinemia type I 2018-04-13 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 88 of the ASS1 protein (p.Leu88Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed as homozygous in individuals with elevated citrulline or ASS1 enzyme deficiency in skin fibroblasts (PMID: 18925679, Invitae), findings that are highly specific for ASS1-related disease. ClinVar contains an entry for this variant (Variation ID: 426661). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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