Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002388, PMID:1598908). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000020, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_000045.4(ARG1):c.871C>T (p.Arg291Ter)
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.
(5)
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
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000045.4(ARG1):c.871C>T (p.Arg291Ter)
Variation ID: 2388 Accession: VCV000002388.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q23.2 6: 131583810 (GRCh38) [ NCBI UCSC ] 6: 131904950 (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 Feb 14, 2024 Aug 10, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000045.4:c.871C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000036.2:p.Arg291Ter nonsense NM_001244438.2:c.895C>T NP_001231367.1:p.Arg299Ter nonsense NM_001270521.2:c.4077+3899G>A intron variant NM_001369020.1:c.616C>T NP_001355949.1:p.Arg206Ter nonsense NM_015979.4:c.4095+3899G>A intron variant NR_160934.1:n.855C>T non-coding transcript variant NC_000006.12:g.131583810C>T NC_000006.11:g.131904950C>T NG_007086.2:g.15586C>T NG_031860.2:g.49414G>A - Protein change
- R291*, R206*, R299*
- Other names
- -
- Canonical SPDI
- NC_000006.12:131583809:C:T
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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.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
- 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. |
|||
| ARG1 | - | - |
GRCh38 GRCh37 |
40 | 555 | |
| MED23 | - | - |
GRCh38 GRCh37 |
187 | 702 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Aug 10, 2023 | RCV000002489.18 |
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
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Arginase deficiency
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002059070.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002388, PMID:1598908). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000020, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Conjugated hyperbilirubinemia (present) , Hyperargininemia (present) , Hyperammonemia (present)
|
|
|
Likely pathogenic
(Feb 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Arginase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000788449.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
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Pathogenic
(Jun 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Arginase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004208515.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
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Pathogenic
(Aug 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Arginase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000756220.6
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg291*) in the ARG1 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg291*) in the ARG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the ARG1 protein. This variant is present in population databases (rs104893940, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with arginase deficiency (PMID: 1598908, 19052914, 24103480; 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: 2388). This variant disrupts a region of the ARG1 protein in which other variant(s) (p.Lys313Serfs*22) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Jun 01, 1992)
|
no assertion criteria provided
Method: literature only
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ARGININEMIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022647.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a patient with arginase deficiency (207800), Grody et al. (1992) identified a homozygous mutation in the ARG1 gene, resulting in an arg291-to-ter (R291X) substitution.
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg291*) in the ARG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the ARG1 protein. This variant is present in population databases (rs104893940, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with arginase deficiency (PMID: 1598908, 19052914, 24103480; 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: 2388). This variant disrupts a region of the ARG1 protein in which other variant(s) (p.Lys313Serfs*22) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002388, PMID:1598908). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000020, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change creates a premature translational stop signal (p.Arg291*) in the ARG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the ARG1 protein. This variant is present in population databases (rs104893940, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with arginase deficiency (PMID: 1598908, 19052914, 24103480; 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: 2388). This variant disrupts a region of the ARG1 protein in which other variant(s) (p.Lys313Serfs*22) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency. | Huemer M | Journal of inherited metabolic disease | 2016 | PMID: 27038030 |
| Novel complex re-arrangement of ARG1 commonly shared by unrelated patients with hyperargininemia. | Mohseni J | Gene | 2014 | PMID: 24103480 |
| Studies on the functional significance of a C-terminal S-shaped motif in human arginase type I: essentiality for cooperative effects. | García D | Archives of biochemistry and biophysics | 2009 | PMID: 18957279 |
| Amino acids in CSF and plasma in hyperammonaemic coma due to arginase1 deficiency. | Scholl-Bürgi S | Journal of inherited metabolic disease | 2008 | PMID: 19052914 |
| Loss of function mutations in conserved regions of the human arginase I gene. | Vockley JG | Biochemical and molecular medicine | 1996 | PMID: 8902193 |
| Molecular genetic study of human arginase deficiency. | Grody WW | American journal of human genetics | 1992 | PMID: 1598908 |
Text-mined citations for rs104893940 ...
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 Nov 25, 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.