The W179R missense change in the ASS1 gene has been reported multiple times in individuals with argininosuccinate synthetase deficiency and is described as being associated with a mild clinical course with patients often being identified by newborn screening programs (Häberle et al. 2002; Häberle et al. 2003; Gao et al. 2003; Dimmock et al. 2008). Expression of W179R in E.coli found that this variant is associated with intermediate (~6%) residual enzyme activity compared to wild-type (Berning et al. 2008). W179R was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The W179R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret this variant as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_054012.4(ASS1):c.535T>C (p.Trp179Arg)
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.
(14)
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
14
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_054012.4(ASS1):c.535T>C (p.Trp179Arg)
Variation ID: 6335 Accession: VCV000006335.40
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q34.11 9: 130470873 (GRCh38) [ NCBI UCSC ] 9: 133346260 (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 Oct 15, 2016 Oct 20, 2024 Feb 20, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_054012.4:c.535T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_446464.1:p.Trp179Arg missense NM_000050.4:c.535T>C NP_000041.2:p.Trp179Arg missense NC_000009.12:g.130470873T>C NC_000009.11:g.133346260T>C NG_011542.1:g.31167T>C P00966:p.Trp179Arg - Protein change
- W179R
- Other names
- -
- Canonical SPDI
- NC_000009.12:130470872:T:C
-
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.
-
0.00020 (C)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00009
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- 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. |
|||
| ASS1 | - | - |
GRCh38 GRCh37 |
819 | 871 | |
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 (1) |
no assertion criteria provided
|
Apr 1, 2002 | RCV000006707.12 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 1, 2021 | RCV000291508.29 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Feb 20, 2024 | RCV000256312.26 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 5, 2023 | RCV001376556.13 | |
|
ASS1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jul 10, 2024 | RCV003914816.2 |
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
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia type I
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001810274.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
|
|
Pathogenic
(Jan 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia type I
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002800243.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Sep 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia type I
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002019989.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Aug 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329824.5
First in ClinVar: Dec 06, 2016 Last updated: Dec 19, 2017 |
Comment:
The W179R missense change in the ASS1 gene has been reported multiple times in individuals with argininosuccinate synthetase deficiency and is described as being associated … (more)
The W179R missense change in the ASS1 gene has been reported multiple times in individuals with argininosuccinate synthetase deficiency and is described as being associated with a mild clinical course with patients often being identified by newborn screening programs (Häberle et al. 2002; Häberle et al. 2003; Gao et al. 2003; Dimmock et al. 2008). Expression of W179R in E.coli found that this variant is associated with intermediate (~6%) residual enzyme activity compared to wild-type (Berning et al. 2008). W179R was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The W179R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret this variant as pathogenic. (less)
|
|
|
Pathogenic
(Dec 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000834604.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 179 of the ASS1 protein … (more)
This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 179 of the ASS1 protein (p.Trp179Arg). This variant is present in population databases (rs121908646, gnomAD 0.01%). This missense change has been observed in individual(s) with citrullinemia (PMID: 11941481, 12815590, 14680976, 18925679). ClinVar contains an entry for this variant (Variation ID: 6335). 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 ASS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ASS1 function (PMID: 18473344). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
|
Citrullinemia type I
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005052011.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Feb 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia type I
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001163226.2
First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jun 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001747006.20
First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 01, 2002)
|
no assertion criteria provided
Method: literature only
|
CITRULLINEMIA, MILD
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026898.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 20, 2016 |
Comment on evidence:
In 2 sibs of each of 2 families, Haberle et al. (2002) identified a T-to-C transition at nucleotide 535 of the ASS gene, resulting in … (more)
In 2 sibs of each of 2 families, Haberle et al. (2002) identified a T-to-C transition at nucleotide 535 of the ASS gene, resulting in a trp179-to-arg substitution, associated with mild citrullinemia (see 215700). Both families were of Turkish extraction and the parents were consanguineous. Three of the affected children were asymptomatic. The fourth had mild mental retardation. There was no hyperammonemia in any of the 4. Enzyme assays showed levels of activity varying from 7 to 26%. The plasma levels of citrulline were considerably lower than in classic citrullinemia. (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Citrullinemia type I
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453084.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(Jul 10, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ASS1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004730070.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The ASS1 c.535T>C variant is predicted to result in the amino acid substitution p.Trp179Arg. This variant has been documented in patients with citrullinemia type I … (more)
The ASS1 c.535T>C variant is predicted to result in the amino acid substitution p.Trp179Arg. This variant has been documented in patients with citrullinemia type I (e.g., Haberle et al. 2002. PubMed ID: 11941481; Gao et al. 2003. PubMed ID: 12815590; Berning et al. 2008. PubMed ID: 18473344; Dimmock et al. 2008. PubMed ID: 18925679; Table S1 in Diez-Fernandez et al. 2017. PubMed ID: 28111830), and the p.Trp179Arg substitution was found to reduce enzyme activity using in vitro studies (Haberle et al. 2002. PubMed ID: 11941481; Berning et al. 2008. PubMed ID: 18473344). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has been interpreted as pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6335). Based on the collective evidence, this variant is interpreted as pathogenic. (less)
|
|
|
Likely pathogenic
(Jan 19, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Citrullinemia type I
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV001132123.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Citrullinemia type I
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000323094.2
First in ClinVar: Oct 15, 2016 Last updated: Oct 01, 2022 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Citrullinemia type I
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect, ClinGen
Accession: SCV000607233.1
First in ClinVar: Oct 14, 2017 Last updated: Oct 14, 2017 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Premature birth (present) , Abnormal delivery (present) , Hypermetropia (present) , Vertigo (present) , Pectus carinatum (present) , Hip dysplasia (present) , Joint hypermobility (present) … (more)
Premature birth (present) , Abnormal delivery (present) , Hypermetropia (present) , Vertigo (present) , Pectus carinatum (present) , Hip dysplasia (present) , Joint hypermobility (present) , Abnormality of the curvature of the vertebral column (present) , Gastrointestinal dysmotility (present) , Abnormality of the stomach (present) , Abnormality of the bladder (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-01-04
Testing laboratory interpretation: Pathogenic
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 179 of the ASS1 protein (p.Trp179Arg). This variant is present in population databases (rs121908646, gnomAD 0.01%). This missense change has been observed in individual(s) with citrullinemia (PMID: 11941481, 12815590, 14680976, 18925679). ClinVar contains an entry for this variant (Variation ID: 6335). 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 ASS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ASS1 function (PMID: 18473344). For these reasons, this variant has been classified as Pathogenic.
Comment:
The ASS1 c.535T>C variant is predicted to result in the amino acid substitution p.Trp179Arg. This variant has been documented in patients with citrullinemia type I (e.g., Haberle et al. 2002. PubMed ID: 11941481; Gao et al. 2003. PubMed ID: 12815590; Berning et al. 2008. PubMed ID: 18473344; Dimmock et al. 2008. PubMed ID: 18925679; Table S1 in Diez-Fernandez et al. 2017. PubMed ID: 28111830), and the p.Trp179Arg substitution was found to reduce enzyme activity using in vitro studies (Haberle et al. 2002. PubMed ID: 11941481; Berning et al. 2008. PubMed ID: 18473344). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has been interpreted as pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6335). Based on the collective evidence, this variant is interpreted as pathogenic.
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
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 W179R missense change in the ASS1 gene has been reported multiple times in individuals with argininosuccinate synthetase deficiency and is described as being associated with a mild clinical course with patients often being identified by newborn screening programs (Häberle et al. 2002; Häberle et al. 2003; Gao et al. 2003; Dimmock et al. 2008). Expression of W179R in E.coli found that this variant is associated with intermediate (~6%) residual enzyme activity compared to wild-type (Berning et al. 2008). W179R was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The W179R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret this variant as pathogenic.
Comment:
This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 179 of the ASS1 protein (p.Trp179Arg). This variant is present in population databases (rs121908646, gnomAD 0.01%). This missense change has been observed in individual(s) with citrullinemia (PMID: 11941481, 12815590, 14680976, 18925679). ClinVar contains an entry for this variant (Variation ID: 6335). 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 ASS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ASS1 function (PMID: 18473344). For these reasons, this variant has been classified as Pathogenic.
Comment:
The ASS1 c.535T>C variant is predicted to result in the amino acid substitution p.Trp179Arg. This variant has been documented in patients with citrullinemia type I (e.g., Haberle et al. 2002. PubMed ID: 11941481; Gao et al. 2003. PubMed ID: 12815590; Berning et al. 2008. PubMed ID: 18473344; Dimmock et al. 2008. PubMed ID: 18925679; Table S1 in Diez-Fernandez et al. 2017. PubMed ID: 28111830), and the p.Trp179Arg substitution was found to reduce enzyme activity using in vitro studies (Haberle et al. 2002. PubMed ID: 11941481; Berning et al. 2008. PubMed ID: 18473344). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has been interpreted as pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6335). Based on the collective evidence, this variant is interpreted as pathogenic.
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Citrullinemia Type I. | Adam MP | - | 2022 | PMID: 20301631 |
| Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations. | Diez-Fernandez C | Human mutation | 2017 | PMID: 28111830 |
| Cross-sectional observational study of 208 patients with non-classical urea cycle disorders. | Rüegger CM | Journal of inherited metabolic disease | 2014 | PMID: 23780642 |
| 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 |
| Mild citrullinemia in Caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1). | Häberle J | Molecular genetics and metabolism | 2003 | PMID: 14680976 |
| 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 |
| Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia. | Häberle J | Human genetics | 2002 | PMID: 11941481 |
Text-mined citations for rs121908646 ...
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.