NM_000048.4(ASL):c.1153C>T (p.Arg385Cys) AND Argininosuccinate lyase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Sep 11, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
9 submissions [Details]
Record status:
current
Accession:
RCV000002502.13

Allele description [Variation Report for NM_000048.4(ASL):c.1153C>T (p.Arg385Cys)]

NM_000048.4(ASL):c.1153C>T (p.Arg385Cys)

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.1153C>T (p.Arg385Cys)
Other names:
NM_000048.3(ASL):c.1153C>T(p.Arg385Cys); NM_001024943.1(ASL):c.1153C>T(p.Arg385Cys); NM_001024944.1(ASL):c.1093C>T(p.Arg365Cys); NM_001024946.1(ASL):c.1075C>T(p.Arg359Cys)
HGVS:
  • NC_000007.14:g.66092566C>T
  • NG_009288.1:g.21778C>T
  • NM_000048.4:c.1153C>TMANE SELECT
  • NM_001024943.2:c.1153C>T
  • NM_001024944.2:c.1093C>T
  • NM_001024946.2:c.1075C>T
  • NP_000039.2:p.Arg385Cys
  • NP_001020114.1:p.Arg385Cys
  • NP_001020115.1:p.Arg365Cys
  • NP_001020117.1:p.Arg359Cys
  • NC_000007.13:g.65557553C>T
  • NM_000048.3:c.1153C>T
  • NM_001024943.1:c.1153C>T
  • P04424:p.Arg385Cys
Protein change:
R359C; ARG385CYS
Links:
UniProtKB: P04424#VAR_017574; OMIM: 608310.0004; dbSNP: rs28940286
NCBI 1000 Genomes Browser:
rs28940286
Molecular consequence:
  • NM_000048.4:c.1153C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001024943.2:c.1153C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001024944.2:c.1093C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001024946.2:c.1075C>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000022660OMIMno assertion criteria providedPathogenic
(Sep 1, 2002)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000040816GeneReviewsno assertion criteria providedpathologic
(Feb 3, 2011)
not providedcuration

SCV000469783Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely pathogenic
(Apr 28, 2017)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000485615Counsylcriteria provided, single submitter
Likely pathogenic
(Jul 15, 2016)
unknownclinical testing

PubMed (4)
[See all records that cite these PMIDs]

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV000694149Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Feb 2, 2017)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000803479SIB Swiss Institute of Bioinformaticscriteria provided, single submitter
Likely pathogenic
(May 31, 2018)
unknowncuration

PubMed (3)
[See all records that cite these PMIDs]

SCV000953087Invitaecriteria provided, single submitter
Pathogenic
(Sep 11, 2020)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001163192Baylor Geneticscriteria provided, single submitter
Pathogenicgermlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001459679Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing, curation
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providednot providednot providednot providednot providednot providednot providednot providedcuration

Citations

PubMed

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

Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in five unrelated families.

Kleijer WJ, Garritsen VH, Linnebank M, Mooyer P, Huijmans JG, Mustonen A, Simola KO, Arslan-Kirchner M, Battini R, Briones P, Cardo E, Mandel H, Tschiedel E, Wanders RJ, Koch HG.

J Inherit Metab Dis. 2002 Sep;25(5):399-410.

PubMed [citation]
PMID:
12408190
See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000022660.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 2 patients from a family with variable age of onset of ASL deficiency (207900) and considerable residual ASL activity, Kleijer et al. (2002) identified a homozygous 1153C-T transition in the ASL gene, resulting in an arg385-to-cys (R385C) substitution.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV000040816.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000469783.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV000485615.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694149.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From SIB Swiss Institute of Bioinformatics, SCV000803479.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (3)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000953087.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces arginine with cysteine at codon 385 of the ASL protein (p.Arg385Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs28940286, ExAC 0.03%). This variant has been observed as homozygous in several individuals affected with argininosuccinate lyase deficiency (PMID: 12408190, 18616627, 12384776). ClinVar contains an entry for this variant (Variation ID: 2401). Experimental studies have shown that this missense change abrogates argininosuccinate lyase enzymatic activity (PMID: 21667091, 25778938, 26745957). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV001163192.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV001459679.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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