ClinVar Miner

Submissions for variant NM_000048.4(ASL):c.722A>C (p.Glu241Ala)

gnomAD frequency: 0.00001  dbSNP: rs924321091
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000634854 SCV000756206 pathogenic Argininosuccinate lyase deficiency 2023-10-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 241 of the ASL protein (p.Glu241Ala). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with argininosuccinic aciduria (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: 529425). 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. This variant disrupts the p.Glu241 amino acid residue in ASL. Other variant(s) that disrupt this residue have been observed in individuals with ASL-related conditions (PMID: 15164414), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004702222 SCV005205225 uncertain significance not specified 2024-06-14 criteria provided, single submitter clinical testing Variant summary: ASL c.722A>C (p.Glu241Ala) 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 4e-06 in 249206 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.722A>C in individuals affected with Argininosuccinic Aciduria and no experimental evidence demonstrating its impact on protein function have been reported in the literature. ClinVar contains an entry for this variant (Variation ID: 529425). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000634854 SCV002076030 uncertain significance Argininosuccinate lyase deficiency 2020-12-04 no assertion criteria provided clinical testing

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