ClinVar Genomic variation as it relates to human health
NM_054012.4(ASS1):c.539G>A (p.Ser180Asn)
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.539G>A (p.Ser180Asn)
Variation ID: 6326 Accession: VCV000006326.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.11 9: 130470877 (GRCh38) [ NCBI UCSC ] 9: 133346264 (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 Jun 17, 2024 Mar 2, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_054012.4:c.539G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_446464.1:p.Ser180Asn missense NM_000050.4:c.539G>A NP_000041.2:p.Ser180Asn missense NC_000009.12:g.130470877G>A NC_000009.11:g.133346264G>A NG_011542.1:g.31171G>A P00966:p.Ser180Asn - Protein change
- S180N
- Other names
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p.S180N:AGC>AAC
NM_000050.4(ASS1):c.539G>A(p.Ser180Asn)
NM_054012.3(ASS1):c.539G>A(p.Ser180Asn)
- Canonical SPDI
- NC_000009.12:130470876:G:A
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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.
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Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- 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 | ||
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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
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. |
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| ASS1 | - | - |
GRCh38 GRCh37 |
819 | 871 | |
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
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. |
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| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Mar 2, 2024 | RCV000006698.18 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2023 | RCV000185782.4 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV001376618.5 |
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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Pathogenic
(Mar 10, 2017)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694165.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: The ASS1 c.539G>A (p.Ser180Asn) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. … (more)
Variant summary: The ASS1 c.539G>A (p.Ser180Asn) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/121356 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASS1 variant (0.0040825). The variant has been reported in affected individuals in the literature, and was shown in experimental studies to result in ~10% enzyme activity (Diez-Fernandez_2016). Additionally, an internal specimen carrying this variant was specified to have affected cousin who was homozygous for the mutation. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Feb 25, 2022)
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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: SCV000893797.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000238717.12
First in ClinVar: Jul 18, 2015 Last updated: Feb 07, 2023 |
Comment:
Published functional studies found this variant is associated with significantly decreased enzyme activity and thermal stability (Diez-Fernandez C et al., 2016); Not observed at a … (more)
Published functional studies found this variant is associated with significantly decreased enzyme activity and thermal stability (Diez-Fernandez C et al., 2016); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18323623, 31469252, 27287393, 2358466) (less)
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Likely pathogenic
(May 31, 2018)
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criteria provided, single submitter
Method: curation
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Citrullinemia type I
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000803612.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
This variant is interpreted as a Likely Pathogenic, for Citrullinemia 1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines … (more)
This variant is interpreted as a Likely Pathogenic, for Citrullinemia 1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3 => Well-established functional studies show a deleterious effect (PMID:27287393). (less)
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Likely pathogenic
(Apr 28, 2017)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000477626.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The ASS1 c.539G>A (p.Ser180Asn) variant has been reported in a total of three individuals with citrullinemia, all in a compound heterozygous state (Kobayashi et al. … (more)
The ASS1 c.539G>A (p.Ser180Asn) variant has been reported in a total of three individuals with citrullinemia, all in a compound heterozygous state (Kobayashi et al. 1990; Dimmock et al. 2008; Rhee et al. 2013). Control data are not available for this variant, which is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium, though this is based on one allele in a region of good sequencing coverage. Functional studies in E. coli demonstrated the p.Ser180Asn variant had decreased binding affinity for aspartate and citrulline. The activity of the p.Ser180Asn variant increased to approximately 10% of wild type when exposed to large doses of aspartate (Diez-Fernandez et al. 2016). Based on the evidence, the p.Ser180Asn variant is classified as likely pathogenic for citrullinemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Jun 20, 2023)
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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: SCV004238128.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 18, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000630060.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 180 of the ASS1 protein (p.Ser180Asn). … (more)
This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 180 of the ASS1 protein (p.Ser180Asn). This variant is present in population databases (rs121908638, gnomAD 0.008%). This missense change has been observed in individual(s) with citrullinemia type I, including symptoms of hyperammonemia and markedly elevated plasma citrulline (PMID: 2358466, 18925679, 24765495; Invitae). ClinVar contains an entry for this variant (Variation ID: 6326). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 02, 2024)
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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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Baylor Genetics
Accession: SCV001163227.2
First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024 |
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Pathogenic
(Apr 04, 2013)
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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: SCV000026889.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2013 |
Comment on evidence:
Kobayashi et al. (1989) demonstrated a change in codon 180 in the ASS gene, AGC (ser) to AAC (asn), in a case of citrullinemia (215700).
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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
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Kinetic mutations in argininosuccinate synthetase deficiency: characterisation and in vitro correction by substrate supplementation. | Diez-Fernandez C | Journal of medical genetics | 2016 | PMID: 27287393 |
| Citrullinemia type I and hypertrophic pyloric stenosis in a 1-month old male infant. | Rhee Y | Clinics and practice | 2013 | PMID: 24765495 |
| 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 |
| Heterogeneity of mutations in argininosuccinate synthetase causing human citrullinemia. | Kobayashi K | The Journal of biological chemistry | 1990 | PMID: 2358466 |
| Kobayashi, K., Jackson, M. J., Tick, D. B., O'Brien, W. E., Beaudet, A. L. Characterization of nine mutant alleles causing citrullinemia. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A201-only, 1989. | - | - | - | - |
Text-mined citations for rs121908638 ...
HelpRecord 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.