Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000274099 | SCV000469781 | uncertain significance | Argininosuccinate lyase deficiency | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
| Labcorp Genetics |
RCV000274099 | SCV001577811 | likely pathogenic | Argininosuccinate lyase deficiency | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 375 of the ASL protein (p.Tyr375Cys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with argininosuccinic aciduria (PMID: 29773863). ClinVar contains an entry for this variant (Variation ID: 360568). 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%. 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. |
| Revvity Omics, |
RCV000274099 | SCV002024369 | likely pathogenic | Argininosuccinate lyase deficiency | 2021-10-20 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003230485 | SCV003928887 | uncertain significance | not specified | 2023-04-13 | criteria provided, single submitter | clinical testing | Variant summary: ASL c.1124A>G (p.Tyr375Cys) results in a non-conservative amino acid change located in the Argininosuccinate lyase, C-terminal domain (IPR029419) 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 8e-06 in 250094 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1124A>G has been reported in the literature in at least one individual affected with Argininosuccinic Aciduria (e.g., Kim_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments: two submitters classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Fulgent Genetics, |
RCV000274099 | SCV005667427 | likely pathogenic | Argininosuccinate lyase deficiency | 2024-04-17 | criteria provided, single submitter | clinical testing |