ClinVar Genomic variation as it relates to human health
NM_054012.4(ASS1):c.835C>T (p.Arg279Ter)
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
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NM_054012.4(ASS1):c.835C>T (p.Arg279Ter)
Variation ID: 6333 Accession: VCV000006333.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.11 9: 130480446 (GRCh38) [ NCBI UCSC ] 9: 133355833 (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 Apr 8, 2013 Feb 14, 2024 Oct 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_054012.4:c.835C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_446464.1:p.Arg279Ter nonsense NM_000050.4:c.835C>T NP_000041.2:p.Arg279Ter nonsense NC_000009.12:g.130480446C>T NC_000009.11:g.133355833C>T NG_011542.1:g.40740C>T - Protein change
- R279*
- Other names
- -
- Canonical SPDI
- NC_000009.12:130480445: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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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ASS1 | - | - |
GRCh38 GRCh37 |
793 | 842 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Dec 28, 2021 | RCV000006705.25 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 25, 2023 | RCV001376581.4 |
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
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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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Pathogenic
(Aug 29, 2019)
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criteria provided, single submitter
Method: clinical testing
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Citrullinemia type I
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001156647.2
First in ClinVar: Feb 10, 2020 Last updated: Jan 26, 2021 |
Comment:
The ASS1 c.835C>T; p.Arg279Ter variant (rs121908645) has been described in the homozygous and compound heterozygous states in individuals diagnosed with citrullinemia (Gao 2003, Kleijer 2006, … (more)
The ASS1 c.835C>T; p.Arg279Ter variant (rs121908645) has been described in the homozygous and compound heterozygous states in individuals diagnosed with citrullinemia (Gao 2003, Kleijer 2006, Li 2001). It is reported as pathogenic and likely pathogenic in ClinVar (Variation ID: 6333) and observed in the general population at a low overall frequency of 0.0024% (6/245706 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, RNA analysis of this variant in skin fibroblasts from an affected patient demonstrated an RNA-negative allele in which no stable mRNA was detected (Li 2001). Based on available information, this variant is considered pathogenic. References: Gao H et al. Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. Hum Mutat. 2003 Jul;22(1):24-34. Kleijer W et al. Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia. Prenat Diagn. 2006 Mar;26(3):242-7. Li C et al. A nonsense mutation is responsible for the RNA-negative phenotype in human citrullinaemia. Eur J Hum Genet. 2001 Sep;9(9):685-9. (less)
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Likely pathogenic
(Aug 22, 2014)
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criteria provided, single submitter
Method: literature only
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Citrullinemia type I
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220625.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Dec 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Citrullinemia type I
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809909.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Citrullinemia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001222396.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg279*) in the ASS1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg279*) in the ASS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASS1 are known to be pathogenic (PMID: 18473344, 19006241). This variant is present in population databases (rs121908645, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with citrullinemia type 1 (PMID: 11571557, 16475226, 27287393, 28111830). ClinVar contains an entry for this variant (Variation ID: 6333). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Citrullinemia type I
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163592.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
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Pathogenic
(Apr 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Citrullinuria
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338439.1
First in ClinVar: Jun 19, 2020 Last updated: Jun 19, 2020 |
Comment:
Variant summary: ASS1 c.835C>T (p.Arg279X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ASS1 c.835C>T (p.Arg279X) 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 2.4e-05 in 250820 control chromosomes. c.835C>T has been reported in the literature in multiple individuals affected with Citrullinemia Type I (examples- Li_2001, Gao_2003, Kleijer_2006). These data indicate that the variant is very likely to be associated with disease. No stable mRNA was detected from the allele with the variant in RNA isolated from patient skin fibroblasts, presumably due to nonsense-mediated decay (Li_2001). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Dec 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Citrullinemia type I
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003814426.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 01, 2001)
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no assertion criteria provided
Method: literature only
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CITRULLINEMIA, CLASSIC
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026896.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2013 |
Comment on evidence:
In a citrullinemia (215700) patient carrying an RNA-negative allele, Li et al. (2001) described a C-to-T transition at nucleotide 835 in the cDNA of the … (more)
In a citrullinemia (215700) patient carrying an RNA-negative allele, Li et al. (2001) described a C-to-T transition at nucleotide 835 in the cDNA of the ASS gene, converting the CGA arginine codon to a TGA termination codon within exon 12 (R279X). The patient was compound heterozygous for the R279X mutation and the IVS6-2A-G mutation (603470.0003). There was no indication of the R279X mutation leading to altered splicing, and the most likely defect responsible for the mRNA reduction appeared to be nonsense-mediated mRNA decay affecting the abundance of nucleus-associated mRNA. It was estimated that mRNA from the R279X allele was less than 2% of the normal level. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Citrullinemia type I
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001453090.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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 |
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Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations. | Diez-Fernandez C | Human mutation | 2017 | PMID: 28111830 |
Kinetic mutations in argininosuccinate synthetase deficiency: characterisation and in vitro correction by substrate supplementation. | Diez-Fernandez C | Journal of medical genetics | 2016 | PMID: 27287393 |
Molecular genetics of citrullinemia types I and II. | Woo HI | Clinica chimica acta; international journal of clinical chemistry | 2014 | PMID: 24508627 |
Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene. | Engel K | Human mutation | 2009 | PMID: 19006241 |
The role of molecular testing and enzyme analysis in the management of hypomorphic citrullinemia. | Dimmock DP | American journal of medical genetics. Part A | 2008 | PMID: 18925679 |
Investigation of citrullinemia type I variants by in vitro expression studies. | Berning C | Human mutation | 2008 | PMID: 18473344 |
Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia. | Kleijer WJ | Prenatal diagnosis | 2006 | PMID: 16475226 |
Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. | Gao HZ | Human mutation | 2003 | PMID: 12815590 |
A nonsense mutation is responsible for the RNA-negative phenotype in human citrullinaemia. | Li CM | European journal of human genetics : EJHG | 2001 | PMID: 11571557 |
Text-mined citations for rs121908645 ...
HelpRecord last updated Apr 15, 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.