The c.545G>A (p.Arg182Gln) missense variant in the ASL gene has been previously reported in one affected individual with autosomal recessive Argininosuccinic aciduria. The affected individual harbored this missense variant in trans with a canonical splice site variant (IVS5+1G>A) reported to cause a premature protein truncation (Linnebank et al., 2002). Cultured fibroblast from this individual showed the enzyme activity of ASL was less than 2% relative to controls (Linnebank et al., 2002). The c.545G>A variant is located within a mutational hotspot which includes exons 5, 6, and 8 (Linnebank et al., 2002). Functional studies using a yeast complementation assay conclude the Arg182Gln variant is unable to complement relative to controls (Trevisson et al., 2009). The c.545G>A variant has been reported at low frequencies in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAc) and multiple lines of computation evidence suggest a deleterious effect (GERP = 5.65; CADD = 34; polyPhen = 0.997; SIFT = 0). In addition, this variant has been reported as pathogenic in ClinVar by another clinical laboratory. Therefore, this collective evidence supports the classification of the c.545G>A (p.Arg182Gln) as a recessive Pathogenic variant for Argininosuccinic aciduria.
ClinVar Genomic variation as it relates to human health
NM_000048.4(ASL):c.545G>A (p.Arg182Gln)
Germline
Classification
Help
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.
(8)
Help
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.
Pathogenic/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000048.4(ASL):c.545G>A (p.Arg182Gln)
Variation ID: 203613 Accession: VCV000203613.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q11.21 7: 66086764 (GRCh38) [ NCBI UCSC ] 7: 65551751 (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 3, 2017 Jun 17, 2024 Mar 28, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000048.4:c.545G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000039.2:p.Arg182Gln missense NM_001024943.2:c.545G>A NP_001020114.1:p.Arg182Gln missense NM_001024944.2:c.545G>A NP_001020115.1:p.Arg182Gln missense NM_001024946.2:c.524+102G>A intron variant NC_000007.14:g.66086764G>A NC_000007.13:g.65551751G>A NG_009288.1:g.15976G>A P04424:p.Arg182Gln - Protein change
- R182Q
- Other names
- -
- Canonical SPDI
- NC_000007.14:66086763:G:A
-
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) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00006
- Links
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 |
859 | 895 | |
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 (8) |
criteria provided, multiple submitters, no conflicts
|
Mar 28, 2024 | RCV000454306.17 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 04, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: no
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000538014.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
Comment:
The c.545G>A (p.Arg182Gln) missense variant in the ASL gene has been previously reported in one affected individual with autosomal recessive Argininosuccinic aciduria. The affected individual … (more)
The c.545G>A (p.Arg182Gln) missense variant in the ASL gene has been previously reported in one affected individual with autosomal recessive Argininosuccinic aciduria. The affected individual harbored this missense variant in trans with a canonical splice site variant (IVS5+1G>A) reported to cause a premature protein truncation (Linnebank et al., 2002). Cultured fibroblast from this individual showed the enzyme activity of ASL was less than 2% relative to controls (Linnebank et al., 2002). The c.545G>A variant is located within a mutational hotspot which includes exons 5, 6, and 8 (Linnebank et al., 2002). Functional studies using a yeast complementation assay conclude the Arg182Gln variant is unable to complement relative to controls (Trevisson et al., 2009). The c.545G>A variant has been reported at low frequencies in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAc) and multiple lines of computation evidence suggest a deleterious effect (GERP = 5.65; CADD = 34; polyPhen = 0.997; SIFT = 0). In addition, this variant has been reported as pathogenic in ClinVar by another clinical laboratory. Therefore, this collective evidence supports the classification of the c.545G>A (p.Arg182Gln) as a recessive Pathogenic variant for Argininosuccinic aciduria. (less)
|
|
|
Likely pathogenic
(Aug 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000793576.1
First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinic aciduria
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001424362.1
First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020 |
|
|
|
Pathogenic
(Feb 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003932319.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
PS3, PM3, PM2, PM1, PP3
|
|
|
Likely pathogenic
(Feb 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003809856.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000829269.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 182 of the ASL protein (p.Arg182Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 182 of the ASL protein (p.Arg182Gln). This variant is present in population databases (rs751590073, gnomAD 0.005%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 19703900, 24166829; Invitae; RQ355872). 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: 203613). 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: 19703900). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Mar 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001163190.2
First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001459676.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
PS3, PM3, PM2, PM1, PP3
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 182 of the ASL protein (p.Arg182Gln). This variant is present in population databases (rs751590073, gnomAD 0.005%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 19703900, 24166829; Invitae; RQ355872). 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: 203613). 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: 19703900). For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
The c.545G>A (p.Arg182Gln) missense variant in the ASL gene has been previously reported in one affected individual with autosomal recessive Argininosuccinic aciduria. The affected individual harbored this missense variant in trans with a canonical splice site variant (IVS5+1G>A) reported to cause a premature protein truncation (Linnebank et al., 2002). Cultured fibroblast from this individual showed the enzyme activity of ASL was less than 2% relative to controls (Linnebank et al., 2002). The c.545G>A variant is located within a mutational hotspot which includes exons 5, 6, and 8 (Linnebank et al., 2002). Functional studies using a yeast complementation assay conclude the Arg182Gln variant is unable to complement relative to controls (Trevisson et al., 2009). The c.545G>A variant has been reported at low frequencies in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAc) and multiple lines of computation evidence suggest a deleterious effect (GERP = 5.65; CADD = 34; polyPhen = 0.997; SIFT = 0). In addition, this variant has been reported as pathogenic in ClinVar by another clinical laboratory. Therefore, this collective evidence supports the classification of the c.545G>A (p.Arg182Gln) as a recessive Pathogenic variant for Argininosuccinic aciduria.
Comment:
PS3, PM3, PM2, PM1, PP3
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 182 of the ASL protein (p.Arg182Gln). This variant is present in population databases (rs751590073, gnomAD 0.005%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 19703900, 24166829; Invitae; RQ355872). 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: 203613). 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: 19703900). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutations and polymorphisms in the human argininosuccinate lyase (ASL) gene. | Balmer C | Human mutation | 2014 | PMID: 24166829 |
| Epilepsy and argininosuccinic aciduria. | Grioni D | Neuropediatrics | 2011 | PMID: 21744316 |
| Functional complementation in yeast allows molecular characterization of missense argininosuccinate lyase mutations. | Trevisson E | The Journal of biological chemistry | 2009 | PMID: 19703900 |
| Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene. | Linnebank M | Human genetics | 2002 | PMID: 12384776 |
Text-mined citations for rs751590073 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.