ClinVar Genomic variation as it relates to human health
NM_000303.3(PMM2):c.640-9T>G
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.640-9T>G
Variation ID: 632945 Accession: VCV000632945.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.2 16: 8847715 (GRCh38) [ NCBI UCSC ] 16: 8941572 (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 Jun 2, 2019 Jun 17, 2024 Nov 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000303.3:c.640-9T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000016.10:g.8847715T>G NC_000016.9:g.8941572T>G NG_009209.1:g.54903T>G - Protein change
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- Other names
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- Canonical SPDI
- NC_000016.10:8847714:T: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
- 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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PMM2 | - | - |
GRCh38 GRCh37 |
804 | 904 |
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/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Nov 9, 2023 | RCV000780609.14 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
(Oct 18, 2021)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918025.2
First in ClinVar: Jun 02, 2019 Last updated: Nov 20, 2021 |
Comment:
Variant summary: PMM2 c.640-9T>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: PMM2 c.640-9T>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 3 acceptor site. Experimental evidence supports these predictions demonstrating that the variant affects mRNA splicing (Vega_2009). The variant allele was found at a frequency of 4e-06 in 251000 control chromosomes (gnomAD). c.640-9T>G has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a (e.g. Richard_2009, Perez_2011, Perez-Cerda_2017). These data indicate that the variant is likely to be associated with disease. A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 29, 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:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001387044.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 7 of the PMM2 gene. It does not directly change the encoded amino acid sequence of the PMM2 protein. … (more)
This sequence change falls in intron 7 of the PMM2 gene. It does not directly change the encoded amino acid sequence of the PMM2 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs370160676, gnomAD 0.003%). This variant has been observed in individual(s) with congenital disorder of glycosylation type 1a (PMID: 19235233). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 632945). Studies have shown that this variant results in skipping of exon 8 and introduces a new termination codon (PMID: 19235233). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 09, 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: SCV001163406.2
First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Nov 08, 2021)
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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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Myriad Genetics, Inc.
Accession: SCV002060136.2
First in ClinVar: Jan 15, 2022 Last updated: Dec 24, 2022 |
Comment:
NM_000303.2(PMM2):c.640-9T>G is an intronic variant classified as likely pathogenic in the context of congenital disorder of glycosylation type Ia. c.640-9T>G has been observed in cases … (more)
NM_000303.2(PMM2):c.640-9T>G is an intronic variant classified as likely pathogenic in the context of congenital disorder of glycosylation type Ia. c.640-9T>G has been observed in cases with relevant disease (PMID: 29701302, 19235233). Functional assessments of this variant are available in the literature (PMID: 19235233, 21541725). c.640-9T>G has been observed in population frequency databases (gnomAD: NFE 0.001%). In summary, NM_000303.2(PMM2):c.640-9T>G is an intronic variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(May 10, 2022)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002787067.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 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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High-resolution capillary zone electrophoresis for transferrin glycoform analysis associated with congenital disorders of glycosylation. | Tobler M | Journal of separation science | 2018 | PMID: 29701302 |
A Population-Based Study on Congenital Disorders of Protein N- and Combined with O-Glycosylation Experience in Clinical and Genetic Diagnosis. | Pérez-Cerdá C | The Journal of pediatrics | 2017 | PMID: 28139241 |
The molecular landscape of phosphomannose mutase deficiency in iberian peninsula: identification of 15 population-specific mutations. | Pérez B | JIMD reports | 2011 | PMID: 23430838 |
Expression analysis revealing destabilizing mutations in phosphomannomutase 2 deficiency (PMM2-CDG): expression analysis of PMM2-CDG mutations. | Vega AI | Journal of inherited metabolic disease | 2011 | PMID: 21541725 |
Functional analysis of three splicing mutations identified in the PMM2 gene: toward a new therapy for congenital disorder of glycosylation type Ia. | Vega AI | Human mutation | 2009 | PMID: 19235233 |
Congenital disorder of glycosylation Ia: new differentially expressed proteins identified by 2-DE. | Richard E | Biochemical and biophysical research communications | 2009 | PMID: 19101518 |
Text-mined citations for rs370160676 ...
HelpRecord last updated Jan 13, 2025
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.