Submissions for variant NM_000048.4(ASL):c.767T>C (p.Met256Thr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002943663	SCV003277453	pathogenic	Argininosuccinate lyase deficiency	2024-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 256 of the ASL protein (p.Met256Thr). This variant is present in population databases (rs149057077, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of argininosuccinate lyase deficiency (PMID: 24166829; Invitae). ClinVar contains an entry for this variant (Variation ID: 2066939). 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	RCV003388135	SCV004100266	uncertain significance	not specified	2023-09-05	criteria provided, single submitter	clinical testing	Variant summary: ASL c.767T>C (p.Met256Thr) 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 2e-05 in 251122 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.767T>C has been reported in the literature in an individual affected with Argininosuccinic Aciduria (example: Balmer_2014). These data do not allow any conclusion about variant significance. The following publication has been ascertained in the context of this evaluation (PMID: 24166829). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.