NM_000048.4(ASL):c.437G>C (p.Arg146Pro) AND Argininosuccinate lyase deficiency

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 29, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002045721.4

Allele description [Variation Report for NM_000048.4(ASL):c.437G>C (p.Arg146Pro)]

NM_000048.4(ASL):c.437G>C (p.Arg146Pro)

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.437G>C (p.Arg146Pro)

HGVS:

NC_000007.14:g.66083165G>C
NG_009288.1:g.12377G>C
NM_000048.4:c.437G>CMANE SELECT
NM_001024943.2:c.437G>C
NM_001024944.2:c.437G>C
NM_001024946.2:c.437G>C
NP_000039.2:p.Arg146Pro
NP_001020114.1:p.Arg146Pro
NP_001020115.1:p.Arg146Pro
NP_001020117.1:p.Arg146Pro
NC_000007.13:g.65548152G>C

Protein change:

R146P

Links:

dbSNP: rs796051931

NCBI 1000 Genomes Browser:

rs796051931

Molecular consequence:

NM_000048.4:c.437G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001024943.2:c.437G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001024944.2:c.437G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001024946.2:c.437G>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; Human Phenotype Ontology: HP:0025630

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002305294	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24166829, 28251416, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002305294

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 29, 2024)

germline

clinical testing

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

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

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

Expanding the phenotype in argininosuccinic aciduria: need for new therapies.

Baruteau J, Jameson E, Morris AA, Chakrapani A, Santra S, Vijay S, Kocadag H, Beesley CE, Grunewald S, Murphy E, Cleary M, Mundy H, Abulhoul L, Broomfield A, Lachmann R, Rahman Y, Robinson PH, MacPherson L, Foster K, Chong WK, Ridout DA, Bounford KM, et al.

J Inherit Metab Dis. 2017 May;40(3):357-368. doi: 10.1007/s10545-017-0022-x. Epub 2017 Mar 1.

PubMed [citation]

PMID:: 28251416
PMCID:: PMC5393288

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002305294.3

#	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 proline, which is neutral and non-polar, at codon 146 of the ASL protein (p.Arg146Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (Invitae). ClinVar contains an entry for this variant (Variation ID: 1512721). 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%. This variant disrupts the p.Arg146 amino acid residue in ASL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24166829, 28251416). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Last Updated: Sep 29, 2024

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