rs28940286

chr7-66092566-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000048.4(ASL):c.1153C>T(p.Arg385Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000491 in 1,609,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R385H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: ASL NM_000048.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 1.26

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 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 chr7-66092567-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 7-66092566-C-T is Pathogenic according to our data. Variant chr7-66092566-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-66092566-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASL	NM_000048.4	c.1153C>T	p.Arg385Cys	missense_variant	16/17	ENST00000304874.14
ASL	NM_001024943.2	c.1153C>T	p.Arg385Cys	missense_variant	15/16
ASL	NM_001024944.2	c.1093C>T	p.Arg365Cys	missense_variant	14/15
ASL	NM_001024946.2	c.1075C>T	p.Arg359Cys	missense_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASL	ENST00000304874.14	c.1153C>T	p.Arg385Cys	missense_variant	16/17	1	NM_000048.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000766 AC: 19 AN: 247934 Hom.: 0 AF XY: 0.0000818 AC XY: 11 AN XY: 134486

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000363

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000473 AC: 69 AN: 1457236 Hom.: 0 Cov.: 32 AF XY: 0.0000496 AC XY: 36 AN XY: 725094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000503

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74290

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000844 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:10 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 19, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 15, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The ASL c.1153C>T (p.Arg385Cys) missense variant has been reported in at least five studies and is found in a total of 15 individuals with argininosuccinate lyase deficiency, including five who carried the variant in a homozygous state, two with the variant in a compound heterozygous state, and an additional eight individuals where zygosity is unclear (Kleijer et al. 2002; Keskinen et al. 2008; Balmer et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in E.coli, HEK 293T cells and cultured patient fibroblasts show that the variant results in reduced enzyme activity of 0-12% compared to wild type (Kleijer et al. 2002; Engel et al. 2012; Hu et al. 2015). The Arg385 residue is located near the active site and interacts with a glycine residue for stabilization of the protein (Balmer et al. 2014). Based on the evidence, the p.Arg385Cys 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 19, 2021	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Pathogenic, for Argininosuccinic aciduria, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:25778938) (PMID:21667091). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 02, 2017	Variant summary: The ASL c.1153C>T (p.Arg385Cys) variant involves the alteration of a conserved nucleotide indicated to be "located near the active site and interacts with glu389 for with glu389 for stabilization of the carboxy terminus helix bundle and its mutation may impact glu399, which has been proposed as part of active site (via Balmer_2014)." In silico tools, 5/5, predict a damaging outcome, which is supported by mulitple functional studies (Kleijer_2002). The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 8/118832 (1/14858), which does not exceed the estimated maximal expected allele frequency for a pathogenic ASL variant of 1/236. Multiple publications cite the variant in affected individuals, who are homozygous and compound heterozygous, along with authors stating the variant may cause mild to severe phenotypes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 385 of the ASL protein (p.Arg385Cys). This variant is present in population databases (rs28940286, gnomAD 0.07%). This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 12384776, 12408190, 18616627). ClinVar contains an entry for this variant (Variation ID: 2401). 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: 21667091, 25778938, 26745957). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 05, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;D;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Benign	0.72	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;.;H;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.7	D;D;D;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.92
MutPred		0.94		Loss of disorder (P = 0.0292);.;Loss of disorder (P = 0.0292);.;.;
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs28940286; hg19: chr7-65557553; COSMIC: COSV59189094; COSMIC: COSV59189094;