Submissions for variant NM_000048.4(ASL):c.578G>A (p.Arg193Gln)

gnomAD frequency: 0.00004  dbSNP: rs373697663

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413440	SCV000490411	pathogenic	not provided	2016-11-11	criteria provided, single submitter	clinical testing	The R193Q missense variant has reported previously in association with argininosuccinic aciduria (Barbosa et al. 1991; Linnebank et al. 2002). The R193Q variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R193Q variant is a semi-conservative amino acid substitution, it occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant at the same residue (R193W) has also been reported in the Human Gene Mutation Database in association with argininosuccinic aciduria (Stenson et al., 2014), supporting the functional importance of this region of the protein. I summary, we interpret R193Q to be pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000609637	SCV000712578	likely pathogenic	Argininosuccinate lyase deficiency	2017-01-24	criteria provided, single submitter	clinical testing	The p.Arg193Gln (NM_000048.3 c.578G>A) variant in ASL has been reported in 7 com pound heterozygous individuals and 1 homozygous individual with clinical feature s of argininosuccinate lyase deficiency (Barbosa 1991, Kleijer 2002, Linnebank 2 002, and Balmer 2014). This variant has also been identified in 2/22,098 of Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs373697663). In vitro functional studies provide some evidenc e that this variant may impact protein function (Hu 2014); however these types o f assays may not accurately represent biological function. This variant has also been reported in ClinVar (Variation ID#372306). In summary, although additiona l studies are required to fully establish its clinical significance, the p.Arg19 3Gln variant is likely pathogenic for ASL in an autosomal recessive manner based on biallelic observations in patients, impact in functional studies, and low po pulation frequency.
Counsyl	RCV000609637	SCV000790045	likely pathogenic	Argininosuccinate lyase deficiency	2017-03-22	criteria provided, single submitter	clinical testing
Invitae	RCV000609637	SCV001222226	pathogenic	Argininosuccinate lyase deficiency	2023-12-31	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 193 of the ASL protein (p.Arg193Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 705937, 12408190, 24166829). ClinVar contains an entry for this variant (Variation ID: 372306). 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: 25778938). This variant disrupts the p.Arg193 amino acid residue in ASL. Other variant(s) that disrupt this residue have been observed in individuals with ASL-related conditions (PMID: 24166829), 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	RCV000609637	SCV003845149	pathogenic	Argininosuccinate lyase deficiency	2023-02-24	criteria provided, single submitter	clinical testing	Variant summary: ASL c.578G>A (p.Arg193Gln) results in a conservative amino acid change located in the Fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Four 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 201534 control chromosomes. c.578G>A has been reported in the literature in multiple individuals affected with Argininosuccinic Aciduria, and was reported confirmed in trans in at least one patient (example Balmer_2014, Kleijer_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant impacting the same amino acid has been reported in HGMD in association with Argininosuccinate lyase deficiency and has been classified as pathogenic by at least one lab in ClinVar (p.R193W). Six ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=4) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000609637	SCV004040893	pathogenic	Argininosuccinate lyase deficiency	2023-05-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000609637	SCV002076023	pathogenic	Argininosuccinate lyase deficiency	2020-10-15	no assertion criteria provided	clinical testing