Submissions for variant NM_000048.4(ASL):c.437G>A (p.Arg146Gln)

dbSNP: rs796051931

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000673353	SCV001420966	pathogenic	Argininosuccinate lyase deficiency	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 146 of the ASL protein (p.Arg146Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 28251416). 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: 203627). 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%. This variant disrupts the p.Arg146 amino acid residue in ASL. Other variant(s) that disrupt this residue have been observed in individuals with ASL-related conditions (PMID: 24166829, 28251416), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000673353	SCV002060254	uncertain significance	Argininosuccinate lyase deficiency	2021-11-08	criteria provided, single submitter	clinical testing	NM_001024943.1(ASL):c.437G>A(R146Q) is a missense variant classified as a variant of uncertain significance in the context of argininosuccinic aciduria. R146Q has been observed in cases with relevant disease (PMID: 28251416). Functional assessments of this variant are not available in the literature. R146Q has not been observed in population frequency databases. In summary, there is insufficient evidence to classify NM_001024943.1(ASL):c.437G>A(R146Q) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics	RCV000673353	SCV004203062	likely pathogenic	Argininosuccinate lyase deficiency	2024-03-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000673353	SCV002076005	likely pathogenic	Argininosuccinate lyase deficiency	2020-06-17	no assertion criteria provided	clinical testing