NM_000048.4(ASL):c.299T>C (p.Ile100Thr) AND Argininosuccinate lyase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 13, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000587929.4

Allele description [Variation Report for NM_000048.4(ASL):c.299T>C (p.Ile100Thr)]

NM_000048.4(ASL):c.299T>C (p.Ile100Thr)

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.299T>C (p.Ile100Thr)
HGVS:
  • NC_000007.14:g.66082887T>C
  • NG_009288.1:g.12099T>C
  • NM_000048.4:c.299T>CMANE SELECT
  • NM_001024943.2:c.299T>C
  • NM_001024944.2:c.299T>C
  • NM_001024946.2:c.299T>C
  • NP_000039.2:p.Ile100Thr
  • NP_001020114.1:p.Ile100Thr
  • NP_001020115.1:p.Ile100Thr
  • NP_001020117.1:p.Ile100Thr
  • NC_000007.13:g.65547874T>C
  • NM_000048.3:c.299T>C
  • NM_001024943.1:c.299T>C
Protein change:
I100T
Links:
dbSNP: rs202142867
NCBI 1000 Genomes Browser:
rs202142867
Molecular consequence:
  • NM_000048.4:c.299T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001024943.2:c.299T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001024944.2:c.299T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001024946.2:c.299T>C - 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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000694150Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Sep 9, 2016)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000789572Counsylcriteria provided, single submitter
Likely pathogenic
(Feb 13, 2017)
unknownclinical testing

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

Citation Link,

SCV000819747Invitaecriteria provided, single submitter
Likely pathogenic
(Oct 13, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

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

Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene.

Linnebank M, Tschiedel E, Häberle J, Linnebank A, Willenbring H, Kleijer WJ, Koch HG.

Hum Genet. 2002 Oct;111(4-5):350-9. Epub 2002 Aug 14.

PubMed [citation]
PMID:
12384776
See all PubMed Citations (8)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694150.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: The c.299T>C (p.Ile100Thr) in ASL gene is a missense change that alters a highly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00014 (17/118940 chrs tested). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in ASL gene (0.004). The results of functional studies are contradictious, depending on the expression system and ranging from ~90% of residual enzymatic activity in HEK293T to no detectable activity in bacterial cells. Since there is no information from the most reliable functional assay, such as citrulline incorporation was published at the time of evaluation, the results from the other functional assays mentioned above should be taken with caution. The variant was found homozygously or in compound heterozygosity in multiple affected individuals with established diagnosis of ASLD. Taken together, the variant was classified as Pathogenic.

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

From Counsyl, SCV000789572.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000819747.3

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

Description

This sequence change replaces isoleucine with threonine at codon 100 of the ASL protein (p.Ile100Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs202142867, ExAC 0.2%). This variant has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 12384776, 18616627, 22231378). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 495379). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ASL protein function (PMID: 21667091, 25778938, 31943503). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Aug 24, 2021

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