ClinVar Genomic variation as it relates to human health
NM_054012.4(ASS1):c.40G>A (p.Gly14Ser)
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.40G>A (p.Gly14Ser)
Variation ID: 6324 Accession: VCV000006324.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.11 9: 130452268 (GRCh38) [ NCBI UCSC ] 9: 133327655 (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 Feb 8, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_054012.4:c.40G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_446464.1:p.Gly14Ser missense NM_000050.4:c.40G>A NP_000041.2:p.Gly14Ser missense NM_054012.3:c.40G>A NC_000009.12:g.130452268G>A NC_000009.11:g.133327655G>A NG_011542.1:g.12562G>A P00966:p.Gly14Ser - Protein change
- G14S
- Other names
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- Canonical SPDI
- NC_000009.12:130452267: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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The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
- Links
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 |
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
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Feb 8, 2024 | RCV000006696.13 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 5, 2023 | RCV001376548.8 |
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
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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
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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
(Apr 18, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003929006.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
Variant summary: ASS1 c.40G>A (p.Gly14Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: ASS1 c.40G>A (p.Gly14Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251146 control chromosomes (gnomAD). c.40G>A has been reported in the literature in multiple individuals affected with Citrullinemia Type I (Kobayashi_1990, Haberle_2003, Lee_2013, Diez-Fernandez_2016, Diez-Fernandez_2017). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Aug 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Citrullinemia type I
Affected status: no
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000845427.1
First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018 |
Number of individuals with the variant: 1
Sex: female
Geographic origin: Iran
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Likely pathogenic
(Aug 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Citrullinemia type I
Affected status: unknown
Allele origin:
inherited
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002548879.1 First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022 |
Clinical Features:
Seizure (present) , Global developmental delay (present) , Hyperammonemia (present) , Hypoglycemia (present) , Chordee (present) , Hypotonia (present) , Gait imbalance (present)
Secondary finding: no
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Pathogenic
(Dec 05, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001208612.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 14 of the ASS1 protein (p.Gly14Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 14 of the ASS1 protein (p.Gly14Ser). This variant is present in population databases (rs121908636, gnomAD 0.01%). This missense change has been observed in individual(s) with citrullinemia type I (PMID: 2358466, 14680976, 23246278, 27287393, 28111830). ClinVar contains an entry for this variant (Variation ID: 6324). 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
(Feb 08, 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: SCV001163215.2
First in ClinVar: Feb 29, 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: SCV000026887.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2013 |
Comment on evidence:
Kobayashi et al. (1989) demonstrated a change in codon 14 of the ASS gene, GGC (gly) to AGC (ser), in a case of citrullinemia (215700).
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Likely pathogenic
(Jun 01, 2021)
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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: SCV002082215.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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 |
|---|---|---|---|---|
| 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 |
| High prevalence of neonatal presentation in Korean patients with citrullinemia type 1, and their shared mutations. | Lee BH | Molecular genetics and metabolism | 2013 | PMID: 23246278 |
| Mild citrullinemia in Caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1). | Häberle J | Molecular genetics and metabolism | 2003 | PMID: 14680976 |
| 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 rs121908636 ...
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.