Submissions for variant NM_000048.4(ASL):c.311C>T (p.Ala104Val)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV003472661	SCV004203172	likely pathogenic	Argininosuccinate lyase deficiency	2024-03-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003472661	SCV004295212	likely pathogenic	Argininosuccinate lyase deficiency	2023-04-14	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 24166829). 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. 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. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 104 of the ASL protein (p.Ala104Val). This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005062965	SCV005725809	uncertain significance	not specified	2024-11-25	criteria provided, single submitter	clinical testing	Variant summary: ASL c.311C>T (p.Ala104Val) results in a non-conservative amino acid change located in the Argininosuccinate lyase domain (IPR009049) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250540 control chromosomes. c.311C>T has been reported in the literature in compound heterozygous or homozygous individuals affected with Argininosuccinic Aciduria (Balmer_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24166829). ClinVar contains an entry for this variant (Variation ID: 2678665). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.