ClinVar Genomic variation as it relates to human health
NM_000303.3(PMM2):c.647A>T (p.Asn216Ile)
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.647A>T (p.Asn216Ile)
Variation ID: 7707 Accession: VCV000007707.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.2 16: 8847731 (GRCh38) [ NCBI UCSC ] 16: 8941588 (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 Mar 24, 2015 Feb 14, 2024 Jun 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000303.3:c.647A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000294.1:p.Asn216Ile missense NC_000016.10:g.8847731A>T NC_000016.9:g.8941588A>T NG_009209.1:g.54919A>T O15305:p.Asn216Ile - Protein change
- N216I
- Other names
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- Canonical SPDI
- NC_000016.10:8847730:A: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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0.00040 (G)
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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 |
776 | 875 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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 (8) |
criteria provided, multiple submitters, no conflicts
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Jun 22, 2023 | RCV000008146.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 17, 2014 | RCV000724043.4 |
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
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
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
Help
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
(-)
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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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Pediatric Metabolic Diseases, Hacettepe University
Accession: SCV000998569.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
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Pathogenic
(Mar 02, 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500420.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
Variant summary: PMM2 c.647A>T (p.Asn216Ile) 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: PMM2 c.647A>T (p.Asn216Ile) 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 was absent in 251180 control chromosomes. c.647A>T has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a. These data indicate that the variant may 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 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 28, 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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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV002577412.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
PS4, PM1, PM2, PM5, PP2, PP3, PP5
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Pathogenic
(Jul 17, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000232514.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Sep 01, 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: SCV002572753.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007707). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 12905014). A different missense change at the same codon (p.Asn216Ser) has been reported to be associated with PMM2 -related disorder (PMID: 11058896). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Intellectual disability (present) , Global developmental delay (present) , Loss of ambulation (present) , Movement disorder (present) , Gait ataxia (present) , Poor speech (present) … (more)
Intellectual disability (present) , Global developmental delay (present) , Loss of ambulation (present) , Movement disorder (present) , Gait ataxia (present) , Poor speech (present) , Abnormal facial shape (present) , Neurodevelopmental delay (present) , Long face (present) , Thick vermilion border (present) (less)
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Pathogenic
(Jun 17, 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: SCV004205277.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jun 22, 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: SCV000836724.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
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) … (more)
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 PMM2 protein function. Experimental studies have shown that this missense change affects PMM2 function (PMID: 9140401, 25355454). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 7707). This missense change has been observed in individuals with PMM2-congenital disorder of glycosylation (PMID: 9140401, 9497260, 11875054, 12905014, 23430838, 25355454). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 216 of the PMM2 protein (p.Asn216Ile). (less)
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Pathogenic
(Oct 01, 2003)
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no assertion criteria provided
Method: literature only
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CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028351.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 16, 2020 |
Comment on evidence:
For discussion of the asn216-to-ile (N216I) mutation in the PMM2 gene that was found in compound heterozygous state in patients with congenital disorder of glycosylation … (more)
For discussion of the asn216-to-ile (N216I) mutation in the PMM2 gene that was found in compound heterozygous state in patients with congenital disorder of glycosylation type Ia (CDG1A; 212065) by Matthijs et al. (1997), see 601785.0001. Neumann et al. (2003) identified homozygosity for the N216I mutation in a 16-month-old boy with CDG Ia. In contrast to previously reported patients, he had postnatal macrosomia and did not have inverted nipples or abnormal fat pads. His parents, who were consanguineous, were heterozygous for the mutation. The authors suggested that homozygosity for this mutation could have a specific phenotype correlation. (less)
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Pathogenic
(Jul 07, 2021)
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no assertion criteria provided
Method: clinical testing
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Congenital disorder of glycosylation type 1a
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002092446.1
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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A nationwide survey of PMM2-CDG in Italy: high frequency of a mild neurological variant associated with the L32R mutation. | Barone R | Journal of neurology | 2015 | PMID: 25355454 |
The molecular landscape of phosphomannose mutase deficiency in iberian peninsula: identification of 15 population-specific mutations. | Pérez B | JIMD reports | 2011 | PMID: 23430838 |
Congenital disorder of glycosylation type 1a in a macrosomic 16-month-old boy with an atypical phenotype and homozygosity of the N216I mutation. | Neumann LM | European journal of pediatrics | 2003 | PMID: 12905014 |
DHPLC analysis as a platform for molecular diagnosis of congenital disorders of glycosylation (CDG). | Schollen E | European journal of human genetics : EJHG | 2002 | PMID: 12357336 |
A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency. | Westphal V | Human molecular genetics | 2002 | PMID: 11875054 |
High residual activity of PMM2 in patients' fibroblasts: possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency). | Grünewald S | American journal of human genetics | 2001 | PMID: 11156536 |
PMM2 mutation spectrum, including 10 novel mutations, in a large CDG type 1A family material with a focus on Scandinavian families. | Bjursell C | Human mutation | 2000 | PMID: 11058896 |
Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1A. | Matthijs G | American journal of human genetics | 1998 | PMID: 9497260 |
Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). | Matthijs G | Nature genetics | 1997 | PMID: 9140401 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PMM2 | - | - | - | - |
Text-mined citations for rs78290141 ...
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.