NM_000048.4(ASL):c.337C>T (p.Arg113Trp) AND Argininosuccinate lyase deficiency

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Nov 17, 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:: RCV000668492.13

Allele description [Variation Report for NM_000048.4(ASL):c.337C>T (p.Arg113Trp)]

NM_000048.4(ASL):c.337C>T (p.Arg113Trp)

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.337C>T (p.Arg113Trp)

HGVS:

NC_000007.14:g.66082925C>T
NG_009288.1:g.12137C>T
NM_000048.4:c.337C>TMANE SELECT
NM_001024943.2:c.337C>T
NM_001024944.2:c.337C>T
NM_001024946.2:c.337C>T
NP_000039.2:p.Arg113Trp
NP_001020114.1:p.Arg113Trp
NP_001020115.1:p.Arg113Trp
NP_001020117.1:p.Arg113Trp
NC_000007.13:g.65547912C>T
NM_000048.3:c.337C>T
NM_001024943.1:c.337C>T

Protein change:

R113W

Links:

dbSNP: rs767543051

NCBI 1000 Genomes Browser:

rs767543051

Molecular consequence:

NM_000048.4:c.337C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001024943.2:c.337C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001024944.2:c.337C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001024946.2:c.337C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000793106	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Jul 27, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10896281, 24166829 Citation Link,
SCV000962832	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10896281, 24166829, 28492532
SCV002075999	Natera, Inc.	no assertion criteria provided	Pathogenic (Jun 22, 2021)	germline	clinical testing
SCV003934378	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 16, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004208729	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 11, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	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

Citations

PubMed

Two novel mutations (E86A, R113W) in argininosuccinate lyase deficiency and evidence for highly variable splicing of the human argininosuccinate lyase gene.

Linnebank M, Homberger A, Rapp B, Winter C, Marquardt T, Harms E, Koch HG.

J Inherit Metab Dis. 2000 Jun;23(4):308-12. No abstract available.

PubMed [citation]

PMID:: 10896281

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000793106.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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

From Invitae, SCV000962832.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 113 of the ASL protein (p.Arg113Trp). This variant is present in population databases (rs767543051, gnomAD 0.1%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 10896281, 24166829). ClinVar contains an entry for this variant (Variation ID: 553111). 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%. For these reasons, this variant has been 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 Natera, Inc., SCV002075999.1

#	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, SCV003934378.1

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

Description

Variant summary: ASL c.337C>T (p.Arg113Trp) 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 0.00013 in 250038 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ASL causing Argininosuccinic Aciduria (0.00013 vs 0.0042), allowing no conclusion about variant significance. c.337C>T has been reported in the literature in multiple bi-allelic individuals affected with Argininosuccinic Aciduria (example: Balmer_2014). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 24166829). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely 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, SCV004208729.1

#	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: Feb 20, 2024

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