ClinVar Genomic variation as it relates to human health
NM_000303.3(PMM2):c.580C>T (p.Arg194Ter)
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_000303.3(PMM2):c.580C>T (p.Arg194Ter)
Variation ID: 225443 Accession: VCV000225443.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.2 16: 8813047 (GRCh38) [ NCBI UCSC ] 16: 8906904 (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 25, 2017 Feb 14, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000303.3:c.580C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000294.1:p.Arg194Ter nonsense NC_000016.10:g.8813047C>T NC_000016.9:g.8906904C>T NG_009209.1:g.20235C>T - Protein change
- R194*
- Other names
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- Canonical SPDI
- NC_000016.10:8813046:C:T
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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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PMM2 | - | - |
GRCh38 GRCh37 |
758 | 854 |
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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Jan 22, 2024 | RCV000490462.11 |
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
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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
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
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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
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267454.1
First in ClinVar: May 25, 2017 Last updated: May 25, 2017 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Pathogenic
(May 18, 2018)
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criteria provided, single submitter
Method: clinical testing
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Carbohydrate-deficient glycoprotein syndrome type I
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000920015.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: PMM2 c.580C>T (p.Arg194X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: PMM2 c.580C>T (p.Arg194X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was found in the general population at a frequency of 2.4e-05, which is lower than expected for a pathogenic variant in PMM2 causing Congenital Disorder of Glycosylation Type 1a (2.4e-05 vs 0.0056), suggesting that it is not a common polymorphism. The c.580C>T variant has been reported in the literature in individuals with biochemically confirmed Congenital Disorder of Glycosylation Type 1a. These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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PMM2-congenital disorder of glycosylation
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058889.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000024, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000225443, PMID:13129599). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cerebellar hypoplasia (present) , Global developmental delay (present) , Generalized hypotonia (present) , Decreased liver function (present)
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Pathogenic
(Oct 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004204835.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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PMM2-congenital disorder of glycosylation
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001405853.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg194*) in the PMM2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg194*) in the PMM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMM2 are known to be pathogenic (PMID: 19862844). This variant is present in population databases (rs199562225, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with congenital disorder of glycosylation type Ia (PMID: 13129599, 25681648). ClinVar contains an entry for this variant (Variation ID: 225443). For these reasons, this variant has been classified as Pathogenic. (less)
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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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Phenotypic and genotypic spectrum of congenital disorders of glycosylation type I and type II. | Al Teneiji A | Molecular genetics and metabolism | 2017 | PMID: 28122681 |
Application of whole exome sequencing to a rare inherited metabolic disease with neurological and gastrointestinal manifestations: a congenital disorder of glycosylation mimicking glycogen storage disease. | Choi R | Clinica chimica acta; international journal of clinical chemistry | 2015 | PMID: 25681648 |
Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides. | Haeuptle MA | Human mutation | 2009 | PMID: 19862844 |
Different neuroradiological findings during two stroke-like episodes in a patient with a congenital disorder of glycosylation type Ia. | Ishikawa N | Brain & development | 2009 | PMID: 18485644 |
Novel nonsense mutation (R194X) in the PMM2 gene in a Japanese patient with congenital disorder of glycosylation type Ia. | Ono H | Brain & development | 2003 | PMID: 13129599 |
Text-mined citations for rs199562225 ...
HelpRecord last updated Feb 20, 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.