Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000185769 | SCV000238700 | pathogenic | not provided | 2021-08-05 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate that R379C is predicted to affect the stability of the argininosuccinate lyase enzyme and is associated with 10% of wild-type argininosuccinate lyase activity (Hu et al., 2015; Engel et al., 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31943503, 31589614, 32152836, 20236848, 12408190, 27515243, 28643139, 26745957, 24166829, 12384776, 25778938, 21667091, 25087612) |
Eurofins Ntd Llc |
RCV000185769 | SCV000700800 | likely pathogenic | not provided | 2016-12-22 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000002504 | SCV000756207 | pathogenic | Argininosuccinate lyase deficiency | 2024-01-31 | 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 379 of the ASL protein (p.Arg379Cys). This variant is present in population databases (rs28940287, gnomAD 0.01%). This missense change has been observed in individual(s) with argininosuccinic aciduria (PMID: 12408190, 20236848, 27515243; Invitae). 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: 2403). 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: 21667091, 25778938). For these reasons, this variant has been classified as Pathogenic. |
Baylor Genetics | RCV000002504 | SCV001520222 | likely pathogenic | Argininosuccinate lyase deficiency | 2020-03-26 | criteria provided, single submitter | clinical testing | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. |
Fulgent Genetics, |
RCV000002504 | SCV002783514 | pathogenic | Argininosuccinate lyase deficiency | 2021-11-09 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000002504 | SCV002819380 | pathogenic | Argininosuccinate lyase deficiency | 2022-12-09 | criteria provided, single submitter | clinical testing | Variant summary: ASL c.1135C>T (p.Arg379Cys) results in a non-conservative amino acid change in 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 6.4e-05 in 249176 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ASL causing Argininosuccinic Aciduria (6.4e-05 vs 0.0042), allowing no conclusion about variant significance. c.1135C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Argininosuccinic Aciduria (Balmer_2014, Kleijer_2002, Mercimek-Mahmutoglu_2010). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant affects the enzyme stability and results in decreased enzyme activity (Kleijer_2002, Engel_2012, Hu_2015). Six laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
OMIM | RCV000002504 | SCV000022662 | pathogenic | Argininosuccinate lyase deficiency | 2002-09-01 | no assertion criteria provided | literature only | |
Natera, |
RCV000002504 | SCV001459678 | pathogenic | Argininosuccinate lyase deficiency | 2020-09-16 | no assertion criteria provided | clinical testing |