The ASL c.544C>T (p.R182*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been previously observed in the homozygous and compound heterozygous state in individuals with argininosuccinic aciduria (PMID: 17326097; 20298553).
ClinVar Genomic variation as it relates to human health
NM_000048.4(ASL):c.544C>T (p.Arg182Ter)
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.
(10)
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
10
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.544C>T (p.Arg182Ter)
Variation ID: 92362 Accession: VCV000092362.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q11.21 7: 66086763 (GRCh38) [ NCBI UCSC ] 7: 65551750 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 29, 2015 Oct 20, 2024 Feb 16, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000048.4:c.544C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000039.2:p.Arg182Ter nonsense NM_001024943.2:c.544C>T NP_001020114.1:p.Arg182Ter nonsense NM_001024944.2:c.544C>T NP_001020115.1:p.Arg182Ter nonsense NM_001024946.2:c.524+101C>T intron variant NC_000007.14:g.66086763C>T NC_000007.13:g.65551750C>T NG_009288.1:g.15975C>T - Protein change
- R182*
- Other names
- -
- Canonical SPDI
- NC_000007.14:66086762:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00000
The Genome Aggregation Database (gnomAD) 0.00005
- 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 |
858 | 894 | |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 11, 2023 | RCV000078012.31 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Feb 16, 2024 | RCV000194332.22 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Jul 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinic aciduria
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000246572.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
|
|
|
Pathogenic
(Mar 27, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000109850.8
First in ClinVar: Jan 17, 2014 Last updated: Jun 29, 2015 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Argininosuccinate lyase deficiency
Affected status: no
Allele origin:
germline
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251546.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Comment:
carrier finding
|
Comment:
The ASL c.544C>T (p.R182*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been previously observed in the homozygous … (more)
The ASL c.544C>T (p.R182*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been previously observed in the homozygous and compound heterozygous state in individuals with argininosuccinic aciduria (PMID: 17326097; 20298553). (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Nov 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000941192.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg182*) in the ASL gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg182*) in the ASL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASL are known to be pathogenic (PMID: 2263616, 24166829). This variant is present in population databases (rs398123126, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 17326097, 20298553). ClinVar contains an entry for this variant (Variation ID: 92362). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Feb 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004203073.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Dec 23, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000788992.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
|
|
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Pathogenic
(May 25, 2020)
|
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: SCV001370576.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
Variant summary: ASL c.544C>T (p.Arg182X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ASL c.544C>T (p.Arg182X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.8e-06 in 228134 control chromosomes. c.544C>T has been reported in the literature in individuals affected with Argininosuccinic Aciduria and cited by others (example, Trevisson_2007, Imtiaz_2010 and Zielonka_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a complete lack of protein expression (Zielonka_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Oct 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000577475.5
First in ClinVar: Jun 29, 2015 Last updated: Nov 25, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28251416, 18367960, 20298553, 31998365, 25525159, 32778825, 31589614, 24166829, 2263616, 31943503, 17326097) (less)
|
|
|
Pathogenic
(May 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001250343.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001459675.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg182*) in the ASL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASL are known to be pathogenic (PMID: 2263616, 24166829). This variant is present in population databases (rs398123126, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 17326097, 20298553). ClinVar contains an entry for this variant (Variation ID: 92362). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: ASL c.544C>T (p.Arg182X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.8e-06 in 228134 control chromosomes. c.544C>T has been reported in the literature in individuals affected with Argininosuccinic Aciduria and cited by others (example, Trevisson_2007, Imtiaz_2010 and Zielonka_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a complete lack of protein expression (Zielonka_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28251416, 18367960, 20298553, 31998365, 25525159, 32778825, 31589614, 24166829, 2263616, 31943503, 17326097)
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 ASL c.544C>T (p.R182*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been previously observed in the homozygous and compound heterozygous state in individuals with argininosuccinic aciduria (PMID: 17326097; 20298553).
Comment:
This sequence change creates a premature translational stop signal (p.Arg182*) in the ASL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASL are known to be pathogenic (PMID: 2263616, 24166829). This variant is present in population databases (rs398123126, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 17326097, 20298553). ClinVar contains an entry for this variant (Variation ID: 92362). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: ASL c.544C>T (p.Arg182X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.8e-06 in 228134 control chromosomes. c.544C>T has been reported in the literature in individuals affected with Argininosuccinic Aciduria and cited by others (example, Trevisson_2007, Imtiaz_2010 and Zielonka_2020). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a complete lack of protein expression (Zielonka_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28251416, 18367960, 20298553, 31998365, 25525159, 32778825, 31589614, 24166829, 2263616, 31943503, 17326097)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| From genotype to phenotype: Early prediction of disease severity in argininosuccinic aciduria. | Zielonka M | Human mutation | 2020 | PMID: 31943503 |
| Mutations and polymorphisms in the human argininosuccinate lyase (ASL) gene. | Balmer C | Human mutation | 2014 | PMID: 24166829 |
| Novel mutations underlying argininosuccinic aciduria in Saudi Arabia. | Imtiaz F | BMC research notes | 2010 | PMID: 20298553 |
| Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novel ASL pseudogene. | Trevisson E | Human mutation | 2007 | PMID: 17326097 |
| Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region. | Walker DC | Proceedings of the National Academy of Sciences of the United States of America | 1990 | PMID: 2263616 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ASL | - | - | - | - |
Text-mined citations for rs398123126 ...
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 Oct 20, 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.