NM_000048.4(ASL):c.260A>G (p.Asp87Gly) AND Argininosuccinate lyase deficiency

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 31, 2024
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:: RCV000673369.8

Allele description [Variation Report for NM_000048.4(ASL):c.260A>G (p.Asp87Gly)]

NM_000048.4(ASL):c.260A>G (p.Asp87Gly)

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.260A>G (p.Asp87Gly)

HGVS:

NC_000007.14:g.66082420A>G
NG_009288.1:g.11632A>G
NM_000048.4:c.260A>GMANE SELECT
NM_001024943.2:c.260A>G
NM_001024944.2:c.260A>G
NM_001024946.2:c.260A>G
NP_000039.2:p.Asp87Gly
NP_001020114.1:p.Asp87Gly
NP_001020115.1:p.Asp87Gly
NP_001020117.1:p.Asp87Gly
NC_000007.13:g.65547407A>G
NM_001024943.1:c.260A>G

Protein change:

D87G

Links:

dbSNP: rs752100894

NCBI 1000 Genomes Browser:

rs752100894

Molecular consequence:

NM_000048.4:c.260A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001024943.2:c.260A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001024944.2:c.260A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001024946.2:c.260A>G - 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
SCV000798565	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Mar 14, 2018)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15273245, 12384776, 11747432, 24166829, 9045711, 11747433, 9256435 Citation Link,
SCV002271301	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 27, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12384776, 24166829, 11747433, 28492532
SCV005056815	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 31, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000798565

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Mar 14, 2018)

unknown

clinical testing

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

Citation Link,

SCV002271301

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 27, 2023)

germline

clinical testing

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

SCV005056815

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 31, 2024)

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	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

Disruption of a salt bridge dramatically accelerates subunit exchange in duck delta2 crystallin.

Yu B, Paroutis P, Davidson AR, Howell PL.

J Biol Chem. 2004 Sep 24;279(39):40972-9. Epub 2004 Jul 24.

PubMed [citation]

PMID:: 15273245

Three-dimensional structure of the argininosuccinate lyase frequently complementing allele Q286R.

Sampaleanu LM, Vallée F, Thompson GD, Howell PL.

Biochemistry. 2001 Dec 25;40(51):15570-80.

PubMed [citation]

PMID:: 11747432

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000798565.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002271301.3

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 87 of the ASL protein (p.Asp87Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with argininosuccinic aciduria (PMID: 12384776, 24166829). ClinVar contains an entry for this variant (Variation ID: 557253). 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%. Experimental studies have shown that this missense change affects ASL function (PMID: 11747433). 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.

#	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, SCV005056815.1

#	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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