7-66086790-C-G

Variant names:

• chr7-66086790-C-G
• rs143508372
• NM_000048.4:c.571C>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_000048.4(ASL):​c.571C>G​(p.Arg191Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,438,498 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. R191W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 1.78
• Publications: 4 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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000048.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-66086790-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445881.
• 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, 0.801
• PP5: Variant 7-66086790-C-G is Pathogenic according to our data. Variant chr7-66086790-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 692055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASL	NM_000048.4	c.571C>G	p.Arg191Gly	missense_variant	Exon 8 of 17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.571C>G	p.Arg191Gly	missense_variant	Exon 7 of 16		NP_001020114.1
ASL	NM_001024944.2	c.571C>G	p.Arg191Gly	missense_variant	Exon 7 of 15		NP_001020115.1
ASL	NM_001024946.2	c.524+128C>G		intron_variant	Intron 6 of 14		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.571C>G	p.Arg191Gly	missense_variant	Exon 8 of 17	1	NM_000048.4	ENSP00000307188.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000482 AC: 1 AN: 207286 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000638

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1438498 Hom.: 0 Cov.: 32 AF XY: 0.00000280 AC XY: 2 AN XY: 713754

African (AFR) AF: 0.00 AC: 0 AN: 33138

American (AMR) AF: 0.00 AC: 0 AN: 40524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25614

East Asian (EAS) AF: 0.0000518 AC: 2 AN: 38626

South Asian (SAS) AF: 0.00 AC: 0 AN: 83516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101248

Other (OTH) AF: 0.00 AC: 0 AN: 59540

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:2 Uncertain:1

Jan 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 191 of the ASL protein (p.Arg191Gly). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of ASL-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 692055). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASL protein function. This variant disrupts the p.Arg191 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21744316, 24166829, 31943503). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

May 17, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 12, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been previously reported or functionally characterized in the literature to our knowledge. However, a variant involving the same amino acid but resulting in a different missense change (p.Arg191Trp) has been previously reported in an asymptomatic patient with argininosuccinate lyase deficiency detected by newborn screening (PMID: 24166829). The c.571C>G (p.Arg191Gly) variant detected in this individual is present in the heterozygous state in the gnomAD population database at a frequency of 0.0005% (1/201720) and thus is presumed to be rare. Based on the available evidence, the c.571C>G p.Arg191Gly variant is classified as likely pathogenic.

not specified Uncertain:1

Jul 22, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ASL c.571C>G (p.Arg191Gly) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 4.8e-06 in 207286 control chromosomes. c.571C>G has been observed in individual(s) affected with ASL-related conditions (internal data). These data do not allow any conclusion about variant significance. A different variant affecting the same codon has been classified as pathogenic by our lab (c.571C>T, p.Arg191Trp), supporting the critical relevance of codon 191 to ASL protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 692055). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;D;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.0	.;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	2.9	M;M;.;M
PhyloP100		1.8
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Pathogenic	0.76
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.33	T;T;T;T
Vest4		0.46
ClinPred		0.87	D
GERP RS		3.6
Varity_R		0.58
gMVP		0.72
Mutation Taster		=24/76	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs143508372; hg19: chr7-65551777;