ClinVar Genomic variation as it relates to human health
NM_000027.4(AGA):c.346C>T (p.Arg116Trp)
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.346C>T (p.Arg116Trp)
Variation ID: 55942 Accession: VCV000055942.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q34.3 4: 177439624 (GRCh38) [ NCBI UCSC ] 4: 178360778 (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 Jul 24, 2013 Aug 4, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000027.4:c.346C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000018.2:p.Arg116Trp missense NM_001171988.2:c.346C>T NP_001165459.1:p.Arg116Trp missense NR_033655.2:n.408C>T non-coding transcript variant NC_000004.12:g.177439624G>A NC_000004.11:g.178360778G>A NG_011845.2:g.7880C>T - Protein change
- R116W
- Other names
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- Canonical SPDI
- NC_000004.12:177439623: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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 |
525 | 625 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Feb 18, 2024 | RCV000049351.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2024 | RCV004546425.4 |
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
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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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Likely pathogenic
(May 16, 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: SCV001574483.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects AGA function (PMID: 27876883). 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 not expected to disrupt AGA protein function. ClinVar contains an entry for this variant (Variation ID: 55942). This missense change has been observed in individual(s) with aspartylglucosaminuria (PMID: 23271757). This variant is present in population databases (rs386833423, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 116 of the AGA protein (p.Arg116Trp). (less)
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Likely pathogenic
(Feb 18, 2024)
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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: SCV004217772.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Feb 02, 2022)
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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: SCV002104010.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: AGA c.346C>T (p.Arg116Trp) 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.346C>T (p.Arg116Trp) 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 4e-06 in 251442 control chromosomes. c.346C>T has been reported in the literature as a homozygous genotype in three siblings from at-least one consanguineous Turkish family affected with Aspartylglucosaminuria and has been cited by others (example, Opaladen_2014 and Goodspeed_2021). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <5% of normal activity in leukocytes, fibroblasts and in-vitro (example, Opaladen_2014, Banning_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Mar 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV005042519.4
First in ClinVar: May 12, 2024 Last updated: Aug 04, 2024 |
Comment:
AGA: PM2, PM3, PP4, PS3:Supporting
Number of individuals with the variant: 3
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probable-pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Aspartylglycosaminuria
Affected status: not provided
Allele origin:
not provided
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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000081783.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013
Comment:
FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference
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Comment:
Converted during submission to Likely pathogenic.
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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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Aspartylglucosaminuria: Clinical Presentation and Potential Therapies. | Goodspeed K | Journal of child neurology | 2021 | PMID: 33439067 |
Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria. | Banning A | Scientific reports | 2016 | PMID: 27876883 |
Aspartylglucosaminuria: unusual neonatal presentation in Qatari twins with a novel aspartylglucosaminidase gene mutation and 3 new cases in a Turkish family. | Opladen T | Journal of child neurology | 2014 | PMID: 23271757 |
Text-mined citations for rs386833423 ...
HelpRecord last updated Aug 04, 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.