ClinVar Miner

Submissions for variant NM_000026.4(ADSL):c.1342T>C (p.Ser448Pro) (rs771121666)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224729 SCV000280981 likely pathogenic not provided 2016-05-05 criteria provided, single submitter clinical testing
Invitae RCV000526230 SCV000631363 uncertain significance Adenylosuccinate lyase deficiency 2019-11-19 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 448 of the ADSL protein (p.Ser448Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs771121666, ExAC 0.001%). This variant has been reported in combination with another ADSL variants in 2 individuals affected with ADSL-related disease (PMID: 16839792, 24781210). ClinVar contains an entry for this variant (Variation ID: 235410). 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: "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.
GeneDx RCV000224729 SCV000779631 pathogenic not provided 2018-05-31 criteria provided, single submitter clinical testing The S448P pathogenic variant in the ADSL gene has been reported previously in two individuals with adenylosuccinate lyase deficiency, each of whom had a second variant identified in the ADSL gene (Spiegel et al., 2006; Michaud et al., 2014). Biochemical testing in one of these individuals revealed elevated succinyladenosine urinary excretion, confirming dysfunction of adenylosuccinate lyase (ADSL) (Michaud et al., 2014). The S448P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The S448P 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. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with adenylosuccinate lyase deficiency (Stenson et al., 2014). Therefore, S448P is considered a pathogenic variant.

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