ClinVar Miner

Submissions for variant NM_000048.4(ASL):c.283C>T (p.Arg95Cys)

gnomAD frequency: 0.00001  dbSNP: rs28940585
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000002499 SCV001137381 pathogenic Argininosuccinate lyase deficiency 2019-05-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000002499 SCV001214971 pathogenic Argininosuccinate lyase deficiency 2024-04-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 95 of the ASL protein (p.Arg95Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 2263616). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2398). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ASL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ASL function (PMID: 2263616, 9045711, 25778938, 26745957). This variant disrupts the p.Arg95 amino acid residue in ASL. Other variant(s) that disrupt this residue have been observed in individuals with ASL-related conditions (PMID: 2263616, 24166829), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
DASA RCV000002499 SCV002318949 likely pathogenic Argininosuccinate lyase deficiency 2022-03-25 criteria provided, single submitter clinical testing The c.283C>T;p.(Arg95Cys) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 2398; PMID: 2263616; PMID: 25778938; PMID: 26745957; PMID: 9045711)-PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Lyase_1) - PM1. The variant is present at low allele frequencies population databases (rs28940585 – gnomAD 0.0001457%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic
Revvity Omics, Revvity RCV000002499 SCV003810367 likely pathogenic Argininosuccinate lyase deficiency 2022-04-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV000002499 SCV004203161 likely pathogenic Argininosuccinate lyase deficiency 2023-12-30 criteria provided, single submitter clinical testing
OMIM RCV000002499 SCV000022657 pathogenic Argininosuccinate lyase deficiency 1990-12-01 no assertion criteria provided literature only

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