NM_000048.4(ASL):c.706C>T (p.Arg236Trp) AND Argininosuccinate lyase deficiency

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Oct 11, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001210762.13

Allele description [Variation Report for NM_000048.4(ASL):c.706C>T (p.Arg236Trp)]

NM_000048.4(ASL):c.706C>T (p.Arg236Trp)

Gene:

ASL:argininosuccinate lyase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q11.21

Genomic location:

Preferred name:

NM_000048.4(ASL):c.706C>T (p.Arg236Trp)

HGVS:

NC_000007.14:g.66087779C>T
NG_009288.1:g.16991C>T
NM_000048.4:c.706C>TMANE SELECT
NM_001024943.2:c.706C>T
NM_001024944.2:c.706C>T
NM_001024946.2:c.628C>T
NP_000039.2:p.Arg236Trp
NP_001020114.1:p.Arg236Trp
NP_001020115.1:p.Arg236Trp
NP_001020117.1:p.Arg210Trp
NC_000007.13:g.65552766C>T
NM_000048.3:c.706C>T

Protein change:

R210W

Links:

dbSNP: rs761268464

NCBI 1000 Genomes Browser:

rs761268464

Molecular consequence:

NM_000048.4:c.706C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001024943.2:c.706C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001024944.2:c.706C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001024946.2:c.628C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Argininosuccinate lyase deficiency
Synonyms:: Arginino succinase deficiency; Inborn error of urea synthesis, arginino succinic type; Urea cycle disorder, arginino succinase type; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008815; MedGen: C0268547; Orphanet: 23; OMIM: 207900; Human Phenotype Ontology: HP:0025630

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001382265	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 13, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17326097, 19703900, 24166829, 28492532
SCV001429561	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 19, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002076027	Natera, Inc.	no assertion criteria provided	Pathogenic (Dec 4, 2020)	germline	clinical testing
SCV004030117	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 12, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24166829, 19703900, 17326097, 31943503 Citation Link,
SCV004200633	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 11, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Mutations and polymorphisms in the human argininosuccinate lyase (ASL) gene.

Balmer C, Pandey AV, Rüfenacht V, Nuoffer JM, Fang P, Wong LJ, Häberle J.

Hum Mutat. 2014 Jan;35(1):27-35. doi: 10.1002/humu.22469. Epub 2013 Nov 25.

PubMed [citation]

PMID:: 24166829

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001382265.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg236 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24166829; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ASL function (PMID: 19703900). 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. ClinVar contains an entry for this variant (Variation ID: 941054). This missense change has been observed in individual(s) with argininosuccinic aciduria (PMID: 17326097, 19703900, 24166829). This variant is present in population databases (rs761268464, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 236 of the ASL protein (p.Arg236Trp).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429561.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Natera, Inc., SCV002076027.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004030117.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: ASL c.706C>T (p.Arg236Trp) results in a non-conservative amino acid change located in the fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251328 control chromosomes (gnomAD). c.706C>T has been reported in the literature as a biallelic genotype in individuals affected with Argininosuccinic Aciduria, primarily with an early onset of the disease (e.g. Trevisson_2007, Trevisson_2009, Balmer_2014, Zielonka_2020). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function and found the variant effect results in <10% of normal activity (Trevisson_2009, Zielonka_2020). The following publications have been ascertained in the context of this evaluation (PMID: 24166829, 17326097, 19703900, 31943503). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004200633.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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