ClinVar Miner

Submissions for variant NM_000048.4(ASL):c.337C>T (p.Arg113Trp)

gnomAD frequency: 0.00008  dbSNP: rs767543051
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668492 SCV000793106 likely pathogenic Argininosuccinate lyase deficiency 2017-07-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000668492 SCV000962832 pathogenic Argininosuccinate lyase deficiency 2023-11-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 113 of the ASL protein (p.Arg113Trp). This variant is present in population databases (rs767543051, gnomAD 0.1%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 10896281, 24166829). ClinVar contains an entry for this variant (Variation ID: 553111). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000668492 SCV003934378 pathogenic Argininosuccinate lyase deficiency 2023-05-16 criteria provided, single submitter clinical testing Variant summary: ASL c.337C>T (p.Arg113Trp) results in a non-conservative amino acid change located in the Fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 250038 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ASL causing Argininosuccinic Aciduria (0.00013 vs 0.0042), allowing no conclusion about variant significance. c.337C>T has been reported in the literature in multiple bi-allelic individuals affected with Argininosuccinic Aciduria (example: Balmer_2014). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 24166829). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000668492 SCV004208729 pathogenic Argininosuccinate lyase deficiency 2024-02-13 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000668492 SCV005674400 pathogenic Argininosuccinate lyase deficiency 2024-04-29 criteria provided, single submitter clinical testing
Natera, Inc. RCV000668492 SCV002075999 pathogenic Argininosuccinate lyase deficiency 2021-06-22 no assertion criteria provided clinical testing

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