Submissions for variant NM_000048.4(ASL):c.35G>A (p.Arg12Gln)

gnomAD frequency: 0.00120  dbSNP: rs145138923

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078010	SCV000109848	pathogenic	not provided	2013-02-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000078010	SCV000238706	likely pathogenic	not provided	2023-08-28	criteria provided, single submitter	clinical testing	Functional expression studies demonstrate reduced activity of the R12Q variant compared to the wild type protein (Hu et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12384776, 31589614, 11747432, 29773863, 26661037, 25087612, 23757202, 31943503, 20236848, 34405919, 24166829, 25778938, 31980526, 28251416)
Genetic Services Laboratory, University of Chicago	RCV000193312	SCV000246571	pathogenic	Argininosuccinate lyase deficiency	2015-03-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000193312	SCV000469775	pathogenic	Argininosuccinate lyase deficiency	2017-04-27	criteria provided, single submitter	clinical testing	The ASL c.35G>A (p.Arg12Gln) missense variant is reported in two studies in at least nine individuals with argininosuccinate lyase deficiency, including eight compound heterozygotes and one individual in whom zygosity is not noted (Sampaleanu et al. 2001; Balmer et al. 2014). All reported individuals exhibited a mild phenotype. Control data are unavailable for this variant, which is reported at a frequency of 0.00314 in the European American population of the Exome Sequencing Project. Kinetic analysis of the p.Arg12Gln variant by Sampaleanu et al. (2001) showed the Kcat was reduced by 18-fold and the Km was decreased by 2-fold, and Hu et al. (2015) reported that the p.Arg12Gln variant had a specific activity of 4.3% of wild type when expressed in HEK293T cells. Based on the evidence, the p.Arg12Gln variant is classified as pathogenic for argininosuccinate lyase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000078010	SCV000510879	likely pathogenic	not provided	2016-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000193312	SCV000631869	pathogenic	Argininosuccinate lyase deficiency	2024-01-30	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 12 of the ASL protein (p.Arg12Gln). This variant is present in population databases (rs145138923, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with argininosuccinic aciduria (PMID: 20236848, 24166829, 26661037). ClinVar contains an entry for this variant (Variation ID: 92360). 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: 11747432, 25778938). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000193312	SCV000743789	pathogenic	Argininosuccinate lyase deficiency	2017-07-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000193312	SCV000894435	pathogenic	Argininosuccinate lyase deficiency	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000193312	SCV001163189	pathogenic	Argininosuccinate lyase deficiency	2023-07-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000193312	SCV001193779	likely pathogenic	Argininosuccinate lyase deficiency	2021-11-04	criteria provided, single submitter	clinical testing	NM_001024943.1(ASL):c.35G>A(R12Q) is a missense variant classified as likely pathogenic in the context of argininosuccinic aciduria. Please note that R12Q is associated with a broad spectrum of disease, ranging from clinically asymptomatic to classic argininosuccinic aciduria. R12Q has been observed in cases with relevant disease (PMID: 28251416, 24166829, 31943503, 31056765). Functional assessments of this variant are available in the literature (PMID: 11747432, 25778938, 31943503). R12Q has been observed in population frequency databases (gnomAD: NFE 0.19%). In summary, NM_001024943.1(ASL):c.35G>A(R12Q) is a missense variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000078010	SCV001501390	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000193312	SCV001810268	likely pathogenic	Argininosuccinate lyase deficiency	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000193312	SCV002019485	pathogenic	Argininosuccinate lyase deficiency	2021-10-27	criteria provided, single submitter	clinical testing
DASA	RCV000193312	SCV002061272	pathogenic	Argininosuccinate lyase deficiency	2022-01-05	criteria provided, single submitter	clinical testing	The c.35G>A;p.(Arg12Gln) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID 92360; 20236848; 24166829; 28251416) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 25778938) - PS3_supporting. The variant is present at low allele frequencies population databases (rs145138923– gnomAD 0.01163%; ABraOM 0.001281 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg12Gln) was detected in trans with a pathogenic variant (PMID: 20236848: 26661037; 28251416) - PM3_very strong The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 26661037) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV000193312	SCV002503800	likely pathogenic	Argininosuccinate lyase deficiency	2021-08-10	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace arginine with glutamine at codon 12 of the ASL protein (p.(Arg12Gln)). The arginine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the lyase 1 domain. There is a small physicochemical difference between arginine and glutamine. The variant is present in a large population cohort at a frequency of 0.1% (rs145138923, 316/282,204 alleles, 1 homozygote in gnomAD v2.1). The variant has been identified in a homozygous state and compound heterozygous with a second allele in multiple individuals with a phenotype ranging from asymptomatic to agenesis of the corpus callosum or moderate intellectual disability with mild cerebellar atrophy (PMID: 20236848, 24166829, 26661037, 28251416). Impaired enzyme activity has been measured in patient red blood cells and in vitro functional assays expressing the variant (PMID: 11747432, 20236848, 25778938). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PS3_Supporting, PP3, PP4.
New York Genome Center	RCV000193312	SCV002564315	likely pathogenic	Argininosuccinate lyase deficiency	2021-08-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002514370	SCV003716104	pathogenic	Inborn genetic diseases	2021-11-24	criteria provided, single submitter	clinical testing	The c.35G>A (p.R12Q) alteration is located in exon 3 (coding exon 2) of the ASL gene. This alteration results from a G to A substitution at nucleotide position 35, causing the arginine (R) at amino acid position 12 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.11% (316/282204) total alleles studied. The highest observed frequency was 0.19% (244/128664) of European (non-Finnish) alleles. This variant has been reported in the homozygous and compound heterozygous states in several individuals with clinical and/or biochemical features of argininosuccinic acid lyase deficiency (ASLD), although several individuals with reduced enzyme activity were clinically asymptomatic or only mildly affected, which suggests that this variant may be a hypomorphic variant with incomplete penetrance (Mercimek-Mahmutoglu, 2010; Balmer, 2014; Baruteau, 2017). In addition, a recent case-control analysis shows that this alteration is significantly enriched in an ASLD cohort compared to matched controls (Mikó, 2021). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies demonstrate that this alteration leads to reduced enzyme activity when expressed in conjunction with a null allele or in homozygosity (Hu, 2015; Zielonka, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000193312	SCV003807551	pathogenic	Argininosuccinate lyase deficiency	2022-03-18	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000193312	SCV003922687	pathogenic	Argininosuccinate lyase deficiency	2023-03-15	criteria provided, single submitter	clinical testing	Variant summary: ASL c.35G>A (p.Arg12Gln) 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 0.0011 in 250818 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in ASL causing Argininosuccinic Aciduria (0.0011 vs 0.0042), allowing no conclusion about variant significance. c.35G>A has been reported in the literature in multiple individuals affected with Argininosuccinic Aciduria, including at least one homozygote and one case where it was reported as a de novo occurrence (e.g. Mercimek-Mahmutoglu_2010, Balmer_2014, Al-Hashim_2016). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function and both found that the variant effect results in equal to or less than 10% of normal activity (e.g. Sampaleanu_2001, Hu_2015). Sixteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=10)/likely pathogenic (n=6). Based on the evidence outlined above, the variant was classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000193312	SCV003932320	pathogenic	Argininosuccinate lyase deficiency	2023-02-16	criteria provided, single submitter	clinical testing	PM3_Very strong, PS3, PP3
PreventionGenetics, part of Exact Sciences	RCV003415843	SCV004107595	pathogenic	ASL-related condition	2024-02-19	criteria provided, single submitter	clinical testing	The ASL c.35G>A variant is predicted to result in the amino acid substitution p.Arg12Gln. This variant has been reported in the homozygous and compound heterozygous state in individuals with argininosuccinate lyase deficiency (Balmer et al. 2014. PubMed ID: 24166829). In the homozygous state, the p.Arg12Gln substitution was associated with an attenuated course of disease (Balmer et al. 2014. PubMed ID: 24166829). In functional studies, the activity of the argininosuccinate lyase enzyme containing the p.Arg12Gln substitution was decreased relative to wild-type (Sampaleanu et al. 2001. PubMed ID: 11747432; Hu et al. 2015. PubMed ID: 25778938). This variant is reported in 0.19% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Clinical Genetics, Academic Medical Center	RCV000078010	SCV001920450	pathogenic	not provided		no assertion criteria provided	clinical testing