ClinVar Genomic variation as it relates to human health
NM_000027.4(AGA):c.488G>C (p.Cys163Ser)
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_000027.4(AGA):c.488G>C (p.Cys163Ser)
Variation ID: 219 Accession: VCV000000219.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q34.3 4: 177438764 (GRCh38) [ NCBI UCSC ] 4: 178359918 (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 May 8, 2015 Feb 14, 2024 Aug 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000027.4:c.488G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000018.2:p.Cys163Ser missense NM_001171988.2:c.488G>C NP_001165459.1:p.Cys163Ser missense NR_033655.2:n.550G>C non-coding transcript variant NC_000004.12:g.177438764C>G NC_000004.11:g.178359918C>G NG_011845.2:g.8740G>C P20933:p.Cys163Ser - Protein change
- C163S
- Other names
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- Canonical SPDI
- NC_000004.12:177438763:C:G
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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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0.00040 (G)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
The Genome Aggregation Database (gnomAD) 0.00055
Exome Aggregation Consortium (ExAC) 0.00064
The Genome Aggregation Database (gnomAD), exomes 0.00078
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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AGA | - | - |
GRCh38 GRCh37 |
515 | 615 |
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
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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 (1) |
no assertion criteria provided
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Jan 1, 1995 | RCV000000243.3 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Aug 22, 2023 | RCV000410114.17 |
Submissions - Germline
Classification
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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
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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
(Dec 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Aspartylglucosaminuria
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001193819.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000027.3(AGA):c.488G>C(C163S) is classified as pathogenic in the context of aspartylglucosaminuria. Sources cited for classification include the following: PMID 11309371, 1904874, 1559710, 1765378 and 9742145. Classification … (more)
NM_000027.3(AGA):c.488G>C(C163S) is classified as pathogenic in the context of aspartylglucosaminuria. Sources cited for classification include the following: PMID 11309371, 1904874, 1559710, 1765378 and 9742145. Classification of NM_000027.3(AGA):c.488G>C(C163S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Dec 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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Aspartylglucosaminuria
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001467838.1
First in ClinVar: Jan 07, 2021 Last updated: Jan 07, 2021 |
Comment:
Variant summary: AGA c.488G>C (p.Cys163Ser) 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: AGA c.488G>C (p.Cys163Ser) 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 0.00078 in 251288 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.488G>C has been reported in the literature in the compound heterozygous and homozygous state in multiple individuals affected with Aspartylglucosaminuria (Fisher_1991, Ikonen_1991, Tollersrud_1994, Saarela_2001). These data indicate that the variant is very likely to be associated with disease. Functional studies report this variant impaired processing of the precursor molecule into subunits and reduced AGA activity (Fish_1991, Riikonen_1994, Banning_2016). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Aspartylglucosaminuria
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810975.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Aug 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Aspartylglucosaminuria
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001207113.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant is also known as AGAFin. ClinVar contains an entry for this variant (Variation ID: 219). Advanced modeling of protein sequence and biophysical properties … (more)
This variant is also known as AGAFin. ClinVar contains an entry for this variant (Variation ID: 219). 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 AGA protein function. Experimental studies have shown that this missense change affects AGA function (PMID: 1765378, 1904874, 8172656). For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with aspartylglucosaminuria (PMID: 1703489, 1904874, 2011603, 7627186, 11309371, 21228398). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 163 of the AGA protein (p.Cys163Ser). This variant is present in population databases (rs121964904, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. (less)
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Pathogenic
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Aspartylglucosaminuria
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004217638.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 01, 1995)
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no assertion criteria provided
Method: literature only
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ASPARTYLGLUCOSAMINURIA, FINNISH TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000020387.2
First in ClinVar: Apr 04, 2013 Last updated: May 08, 2015 |
Comment on evidence:
By direct sequencing of PCR-amplified AGA cDNA from a patient with aspartylglucosaminuria (AGU; 208400), Ikonen et al. (1991) found a G-to-C mutation resulting in the … (more)
By direct sequencing of PCR-amplified AGA cDNA from a patient with aspartylglucosaminuria (AGU; 208400), Ikonen et al. (1991) found a G-to-C mutation resulting in the substitution of serine for cysteine-163 (C163S). This mutation was found in all of 20 analyzed Finnish AGU patients, and in heterozygous form in all 53 carriers, and in none of 67 control individuals. The mutation produces a change in the predicted flexibility of the AGA polypeptide chain and removes an intramolecular S-S bridge. Fisher et al. (1991) independently found the G-to-C transversion in DNA from Finnish AGU fibroblasts; however, they found a second G-to-A transition that resulted in an arginine-to-glutamine substitution as well. The 2 substitutions were present in all 3 Finnish cases studied and in none of 2 non-Finnish AGU fibroblast lines. In non-Finnish AGU fibroblasts, Fisher et al. (1991) found deletions as the apparent cause of the AGA deficiency. Mononen et al. (1991) likewise found 2 mutations, R161Q and C163S. Both mutations resulted in novel restriction endonuclease sites and were present in all 8 Finnish AGU patients studied, but they were absent from Finnish and non-Finnish controls and a non-Finnish case of AGU. Both amino acid changes would be expected to modify the structure of the protein profoundly: the replacement of an arginine by glutamine represents the substitution of a basic amino acid for one containing an uncharged polar group; the replacement of cysteine by serine may abolish a disulfide bridge. Whether both mutations are involved in the pathologic consequences or whether one mutation is a polymorphism was uncertain. Ikonen et al. (1991) showed by in vitro mutagenesis studies that the C163S mutation is responsible for enzyme deficiency, whereas the arg161-to-gln (R161Q) substitution, which accompanies the other mutation in 98% of AGU alleles in Finland, represents a rare polymorphism. Cysteine-163 was shown to participate in an S-S bridge. The absence of this covalent crosslink in the mutated protein probably results in disturbed folding of the polypeptide chain and consequent decrease in its intracellular stability. Fisher and Aronson (1991) likewise found the 482G-A transition and the 488G-C transversion and demonstrated that only the latter was responsible for deficiency of glycosylasparaginase activity. The substitution prevented the normal posttranslational processing of the precursor polypeptide into its alpha and beta subunits. The C163S mutation is responsible for 98% of the cases of AGU in Finland (Isoniemi et al., 1995). (less)
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Likely pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Aspartylglucosaminuria
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142339.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
Comment:
NM_000027.3:c.488G>C in the AGA gene has an allele frequency of 0.008 in European (Finnish) subpopulation in the gnomAD database. The c.488G>C (p.Cys163Ser) variant has been … (more)
NM_000027.3:c.488G>C in the AGA gene has an allele frequency of 0.008 in European (Finnish) subpopulation in the gnomAD database. The c.488G>C (p.Cys163Ser) variant has been reported previously in the compound heterozygous states (C163S/R161Q) in association with aspartylglucosaminuria (PMID: 1904874; 7627186; 2011603). In vitro functional studies demonstrated that p.Cys163Ser results in deficient enzyme activity (PMID: 1904874; 1765378). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PM3; PS3; PP4. (less)
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Pathogenic
(Oct 14, 2020)
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no assertion criteria provided
Method: clinical testing
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Aspartylglucosaminuria
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002084886.1
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
HelpTitle | Author | Journal | Year | Link |
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Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria. | Banning A | Scientific reports | 2016 | PMID: 27876883 |
Carrier testing for severe childhood recessive diseases by next-generation sequencing. | Bell CJ | Science translational medicine | 2011 | PMID: 21228398 |
Molecular pathogenesis of a disease: structural consequences of aspartylglucosaminuria mutations. | Saarela J | Human molecular genetics | 2001 | PMID: 11309371 |
Expression and endocytosis of lysosomal aspartylglucosaminidase in mouse primary neurons. | Kyttälä A | The Journal of neuroscience : the official journal of the Society for Neuroscience | 1998 | PMID: 9742145 |
Identification of a novel mutation causing aspartylglucosaminuria reveals a mutation hotspot region in the aspartylglucosaminidase gene. | Isoniemi A | Human mutation | 1995 | PMID: 7627186 |
Dissection of the molecular consequences of a double mutation causing a human lysosomal disease. | Riikonen A | DNA and cell biology | 1994 | PMID: 8172656 |
Aspartylglucosaminuria in northern Norway: a molecular and genealogical study. | Tollersrud OK | Journal of medical genetics | 1994 | PMID: 8064811 |
Convenient and quantitative determination of the frequency of a mutant allele using solid-phase minisequencing: application to aspartylglucosaminuria in Finland. | Syvänen AC | Genomics | 1992 | PMID: 1559710 |
Aspartylglycosaminuria in the Finnish population: identification of two point mutations in the heavy chain of glycoasparaginase. | Mononen I | Proceedings of the National Academy of Sciences of the United States of America | 1991 | PMID: 2011603 |
Characterization of the mutation responsible for aspartylglucosaminuria in three Finnish patients. Amino acid substitution Cys163----Ser abolishes the activity of lysosomal glycosylasparaginase and its conversion into subunits. | Fisher KJ | The Journal of biological chemistry | 1991 | PMID: 1904874 |
In vitro mutagenesis helps to unravel the biological consequences of aspartylglucosaminuria mutation. | Ikonen E | Genomics | 1991 | PMID: 1765378 |
Fisher, K. J., Tollersrud, O. K., Aronson, N. N., Jr. Molecular genetics of aspartylglucosaminuria. (Abstract) Nucleic Acids Res. Symp. 23: 8-only, 1991. | - | - | - | - |
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Text-mined citations for rs121964904 ...
HelpRecord last updated Feb 14, 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.