7-66087368-C-T

Variant names:

• chr7-66087368-C-T
• rs761651320
• NM_000048.4:c.637C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000048.4(ASL):​c.637C>T​(p.Arg213*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,454,716 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R213R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: ASL NM_000048.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.61
• Publications: 3 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-66087368-C-T is Pathogenic according to our data. Variant chr7-66087368-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 426366.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.637C>T	p.Arg213*	stop_gained	Exon 9 of 17	ENST00000304874.14	NP_000039.2
ASL	NM_001024943.2	c.637C>T	p.Arg213*	stop_gained	Exon 8 of 16		NP_001020114.1
ASL	NM_001024944.2	c.637C>T	p.Arg213*	stop_gained	Exon 8 of 15		NP_001020115.1
ASL	NM_001024946.2	c.559C>T	p.Arg187*	stop_gained	Exon 7 of 15		NP_001020117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASL	ENST00000304874.14	c.637C>T	p.Arg213*	stop_gained	Exon 9 of 17	1	NM_000048.4	ENSP00000307188.9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000204 AC: 5 AN: 245196 AF XY: 0.0000300

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1454716 Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9 AN XY: 724014

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.0000216 AC: 1 AN: 46352

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

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111964

Other (OTH) AF: 0.0000166 AC: 1 AN: 60338

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Argininosuccinate lyase deficiency Pathogenic:7

Mar 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg213*) in the ASL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASL are known to be pathogenic (PMID: 2263616, 24166829). This variant is present in population databases (rs761651320, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 17326097, 30285816, 31183366). ClinVar contains an entry for this variant (Variation ID: 426366). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Aug 03, 2017

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.637C>T (p.Arg213X) variant results in a premature termination codon, predicted to cause a truncated or absent ASL protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 1/118802 control chromosomes at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASL variant (0.0042258). Multiple publications have cited the variant in affected compound heterozygotes and homozygote individuals. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Feb 13, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 16, 2021

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ASL c.637C>T (p.Arg213Ter) variant is a stop-gained variant that is predicted to result in a premature termination or absence of the protein. The p.Arg213Ter variant is reported in at least eight individuals with argininosuccinate lyase deficiency, including in a homozygous state in one individual and in a compound heterozygous state, most often with a missense variant, in at least seven individuals (Trevisson et al. 2007; Balmer et al. 2014; Bijarnia-Mahay et al. 2018; Zhao et al. 2019; Zhang et al. 2021; Kido et al. 2021). Commonly reported phenotypic features in these individuals included hyperammonemia, elevated argininosuccinic acid, intellectual disability, epilepsy, and hepatic disease. The p.Arg213Ter variant is reported at a frequency of 0.000163 in the South Asian population of the Genome Aggregation Database (version 2.1.1). Transfection of the ASL p.Arg213Ter variant into HEK293T cells resulted in a significantly reduced enzyme activity as compared to cells transfected with the wild type protein (Zhao et al. 2019). Based on the available evidence, the p.Arg213Ter variant is classified as pathogenic for argininosuccinate lyase deficiency. -

Aug 01, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Pathogenic:3

Aug 08, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R213X variant has been reported previously in association with argininosuccinic aciduria (Trevisson et al. 2007). The R213X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R213X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret this variant as pathogenic. -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ASL: PVS1, PM3:Strong, PM2, PP4 -

Nov 30, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.79	D
PhyloP100		2.6
Vest4		0.97
GERP RS		4.8
PromoterAI		-0.0066	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: 18

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

Other links and lift over

dbSNP: rs761651320; hg19: chr7-65552355;