ClinVar Genomic variation as it relates to human health
NM_000048.4(ASL):c.1135C>T (p.Arg379Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000048.4(ASL):c.1135C>T (p.Arg379Cys)
Variation ID: 2403 Accession: VCV000002403.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q11.21 7: 66092078 (GRCh38) [ NCBI UCSC ] 7: 65557065 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Jun 17, 2024 Mar 26, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000048.4:c.1135C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000039.2:p.Arg379Cys missense NM_001024943.2:c.1135C>T NP_001020114.1:p.Arg379Cys missense NM_001024944.2:c.1075C>T NP_001020115.1:p.Arg359Cys missense NM_001024946.2:c.1057C>T NP_001020117.1:p.Arg353Cys missense NC_000007.14:g.66092078C>T NC_000007.13:g.65557065C>T NG_009288.1:g.21290C>T P04424:p.Arg379Cys - Protein change
- R379C, R353C, R359C
- Other names
- p.R379C:CGC>TGC
- Canonical SPDI
- NC_000007.14:66092077:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
ASL | - | - |
GRCh38 GRCh37 |
850 | 886 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 26, 2024 | RCV000002504.14 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 5, 2021 | RCV000185769.8 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Likely pathogenic
(Dec 22, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000700800.2
First in ClinVar: May 29, 2016 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
Pathogenic
(Dec 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002819380.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: ASL c.1135C>T (p.Arg379Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: ASL c.1135C>T (p.Arg379Cys) results in a non-conservative amino acid change in 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 6.4e-05 in 249176 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ASL causing Argininosuccinic Aciduria (6.4e-05 vs 0.0042), allowing no conclusion about variant significance. c.1135C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Argininosuccinic Aciduria (Balmer_2014, Kleijer_2002, Mercimek-Mahmutoglu_2010). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant affects the enzyme stability and results in decreased enzyme activity (Kleijer_2002, Engel_2012, Hu_2015). Six laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
|
Argininosuccinate lyase deficiency
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005052005.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
Likely pathogenic
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001520222.2
First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024 |
|
|
Pathogenic
(Nov 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002783514.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Aug 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000238700.14
First in ClinVar: Jul 18, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that R379C is predicted to affect the stability of the argininosuccinate lyase enzyme and is associated with 10% of wild-type argininosuccinate … (more)
Published functional studies demonstrate that R379C is predicted to affect the stability of the argininosuccinate lyase enzyme and is associated with 10% of wild-type argininosuccinate lyase activity (Hu et al., 2015; Engel et al., 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31943503, 31589614, 32152836, 20236848, 12408190, 27515243, 28643139, 26745957, 24166829, 12384776, 25778938, 21667091, 25087612) (less)
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000756207.6
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 379 of the ASL protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 379 of the ASL protein (p.Arg379Cys). This variant is present in population databases (rs28940287, gnomAD 0.01%). This missense change has been observed in individual(s) with argininosuccinic aciduria (PMID: 12408190, 20236848, 27515243; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2403). 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: 21667091, 25778938). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Sep 01, 2002)
|
no assertion criteria provided
Method: literature only
|
ARGININOSUCCINIC ACIDURIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022662.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 29, 2021 |
Comment on evidence:
In a patient from a family with variable age of onset of ASL deficiency (207900) and considerable residual ASL activity, Kleijer et al. (2002) identified … (more)
In a patient from a family with variable age of onset of ASL deficiency (207900) and considerable residual ASL activity, Kleijer et al. (2002) identified a homozygous 1135C-T transition in the ASL gene, resulting in an arg379-to-cys (R379C) substitution. (less)
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001459678.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Argininosuccinic Acid Lyase Deficiency Missed by Newborn Screen. | Ganetzky RD | JIMD reports | 2017 | PMID: 27515243 |
Unstable argininosuccinate lyase in variant forms of the urea cycle disorder argininosuccinic aciduria. | Hu L | Journal of inherited metabolic disease | 2015 | PMID: 25778938 |
Mutations and polymorphisms in the human argininosuccinate lyase (ASL) gene. | Balmer C | Human mutation | 2014 | PMID: 24166829 |
Bacterial expression of mutant argininosuccinate lyase reveals imperfect correlation of in-vitro enzyme activity with clinical phenotype in argininosuccinic aciduria. | Engel K | Journal of inherited metabolic disease | 2012 | PMID: 21667091 |
Long-term outcome of patients with argininosuccinate lyase deficiency diagnosed by newborn screening in Austria. | Mercimek-Mahmutoglu S | Molecular genetics and metabolism | 2010 | PMID: 20236848 |
Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in five unrelated families. | Kleijer WJ | Journal of inherited metabolic disease | 2002 | PMID: 12408190 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ASL | - | - | - | - |
Text-mined citations for rs28940287 ...
HelpRecord last updated Jun 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.