7-66089114-A-G

Variant names:

• chr7-66089114-A-G
• rs28941472
• NM_000048.4:c.857A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000048.4(ASL):​c.857A>G​(p.Gln286Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q286P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 7.26
• Publications: 25 publications found

Genes affected

ASL (HGNC:746): (argininosuccinate lyase) This gene encodes a member of the lyase 1 family. The encoded protein forms a cytosolic homotetramer and primarily catalyzes the reversible hydrolytic cleavage of argininosuccinate into arginine and fumarate, an essential step in the liver in detoxifying ammonia via the urea cycle. Mutations in this gene result in the autosomal recessive disorder argininosuccinic aciduria, or argininosuccinic acid lyase deficiency. A nontranscribed pseudogene is also located on the long arm of chromosome 22. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ASL Gene-Disease associations (from GenCC):

• argininosuccinic aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000249319 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000048.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-66089114-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2731175.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 95 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 0.7488 (below the threshold of 3.09). Trascript score misZ: 1.388 (below the threshold of 3.09). GenCC associations: The gene is linked to argininosuccinic aciduria.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 7-66089114-A-G is Pathogenic according to our data. Variant chr7-66089114-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000048.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASL	NM_000048.4	MANE Select	c.857A>G	p.Gln286Arg	missense	Exon 12 of 17	NP_000039.2
	ASL	NM_001024943.2		c.857A>G	p.Gln286Arg	missense	Exon 11 of 16	NP_001020114.1
	ASL	NM_001024944.2		c.857A>G	p.Gln286Arg	missense	Exon 11 of 15	NP_001020115.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASL	ENST00000304874.14	TSL:1 MANE Select	c.857A>G	p.Gln286Arg	missense	Exon 12 of 17	ENSP00000307188.9
	ASL	ENST00000395332.8	TSL:1	c.857A>G	p.Gln286Arg	missense	Exon 11 of 16	ENSP00000378741.3
	ENSG00000249319	ENST00000450043.2	TSL:5	c.170A>G	p.Gln57Arg	missense	Exon 3 of 12	ENSP00000396527.2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000120 AC: 30 AN: 250924 AF XY: 0.000110

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000862 AC: 126 AN: 1461684 Hom.: 0 Cov.: 33 AF XY: 0.0000866 AC XY: 63 AN XY: 727166

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86258

European-Finnish (FIN) AF: 0.000263 AC: 14 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000764 AC: 85 AN: 1111934

Other (OTH) AF: 0.0000828 AC: 5 AN: 60386

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152100 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74314

African (AFR) AF: 0.0000965 AC: 4 AN: 41436

American (AMR) AF: 0.000196 AC: 3 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000189

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:13

Jan 18, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 26, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_001024943.1(ASL):c.857A>G(Q286R) is classified as pathogenic in the context of argininosuccinic aciduria. Sources cited for classification include the following: PMID 11747433, 24166829, 15273245, 9686346, 11747432, 19703900, 21667091 and 25778938. Classification of NM_001024943.1(ASL):c.857A>G(Q286R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Nov 03, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The ASL c.857A>G (p.Gln286Arg) variant is indicated to located on the highly conserved and flexible loop C3 comprising residues 270-290 (called 280's loop) that has been proposed to be involved in entry of the substrate and exit of the product at the catalytic center (Balmer_2012) with 4/5 in silico tools predict a damaging outcome, which is further supported by functional studies, Trevisson_2009. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 9/120022 (1/13335), which does not exceed the estimated maximal expected allele frequency for a pathogenic ASL variant of 1/236. The variant of interest has been reported in multiple affected individuals, both as compound heterozygotes and homozygotes, via publications. In addition, multiple databases/clinical diagnostic laboratories have cited the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 12, 2025

Otogenetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3: Well-established in vitro and in vivo functional studies supportive of a damaging effect on the gene and the gene product (PMID 9686346, 19703900, 21667091); PM1: Non-truncating non-synonymous variant located in a critical and well-established functional domain the argininosuccinate lyase (PMID 11092456, 11747432); PM2: Maximum gnomAD MAF of 0.0239% in European-Finnish (FIN) subpopulation (<0.19% threshold); PM3: Variant reported in trans in with another pathogenic variant (ASL c.578G>A, p.Arg193Gln) in an affected individual (PMID: 12408190); PP3: In-silico models predict deleterious effect (Revel = 0.97, BayesDel = 0.57)

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 15, 2020

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 31, 2025

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.009%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19703900). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.97 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002399). A different missense change at the same codon (p.Gln286Pro) has been reported to be associated with ASL-related disorder (ClinVar ID: VCV002731175). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Jun 24, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Aug 30, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the ASL c.857A>G (p.Gln286Arg) missense variant has been identified in a total of 18 individuals with argininosuccinate lyase deficiency, including in nine individuals in a homozygous state, in seven individuals in a compound heterozygous state and in two affected individuals in a heterozygous state in whom a second variant was not identified (Walker et al. 1997; Linnebank et al. 2002; Balmer et al. 2014). In two of the compound heterozygotes the second variant results is a frameshift leading to early termination of the protein and in the remaining four compound heterozygotes it is a missense variant. In the study by Balmer et al. (2014), four of the homozygotes and two of the compound heterozygotes were noted to have neonatal onset of the disease with one of the compound heterozygotes noted to have late onset of the disease. The age of onset for the remaining four homozygotes and four compound heterozygotes was unknown. The variant has been noted to be associated with a severe phenotype (Balmer et al. 2014). The p.Gln286Arg variant was absent from 20 controls (Walker et al. 1997) and is reported at a frequency of 0.00047 in the other population of the Exome Aggregation Consortium. Sampaleanu et al. (2001) note that the Gln286 residue is located in a highly conserved and flexible loop region of the protein that has been proposed to be involved in entry of the substrate and exit of the product at the catalytic center. Substitution of the glutamine at this residue to arginine changes the interactions of this loop and neighbouring residues that may impact catalysis. Expression of the variant p.Gln286Arg protein in COS-1 cells and HEK293T cells resulted in a similar level of protein expression of the correct size compared to wild type (Walker et al. 1997; Hu et al. 2015). However, the variant protein was shown to retain no significant residual enzymatic activity in either patient-derived red blood cells (less than 5%) or fibroblasts (less than 3%) or when expressed in E.coli, COS-1 cells (0.05%), or HEK293T cells (Walker et al. 1997; Balmer et al. 2014; Hu et al. 2015). Based on the collective evidence, the p.Gln286Arg 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.

May 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 286 of the ASL protein (p.Gln286Arg). This variant is present in population databases (rs28941472, gnomAD 0.02%). This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 12408190, 19703900, 21667091, 23430928). ClinVar contains an entry for this variant (Variation ID: 2399). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 9686346, 11747433, 19703900, 21667091). For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:2

Feb 22, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported many times in unrelated patients with argininosuccinic aciduria and has been identified on approximately 8% of ASL pathogenic alleles (PMID: 12384776); 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: 22231378, 12408190, 25778938, 11747433, 21667091, 24166829, 9686346, 30285816, 31943503, 17326097, 31980526, 34426522, 32778825, 31589614, 38198573, 36270249, 9045711, 12384776, 11747432)

Jan 22, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.3
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.61	P
Vest4		0.92
MVP		0.98
MPC		0.89
ClinPred		0.94	D
GERP RS		4.9
PromoterAI		0.12	Neutral
Varity_R		0.94
gMVP		0.87
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28941472; hg19: chr7-65554101;