POMGNT1
protein-codingprotein O-linked mannose N-acetylglucosaminyltransferase 1 (beta 1,2-), the group of O-linked N-acetylglucosaminyltransferases
Gene summary
This gene encodes a type II transmembrane protein that resides in the Golgi apparatus. It participates in O-mannosyl glycosylation and is specific for alpha linked terminal mannose. Mutations in this gene may be associated with muscle-eye-brain disease and several congenital muscular dystrophies. Alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Feb 2014]
- MEB
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~31.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014929
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013155
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009667
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013161
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009667
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009667
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013155
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0018939
Submitter: Myriad Women's Health
Inheritance Pattern: AR
Disease ID:MONDO:0009667
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0018277
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0018939
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0000171
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0700068
Submitter: ClinGen
The relationship between *POMGNT1* and autosomal recessive myopathy caused by variation in *POMGNT1* (muscular dystrophy-dystroglycanopathy types 3A (congenital with brain and eye anomalies) and 3B (congenital with mental retardation) included)), has been evaluated using the ClinGen Clinical Validity Framework as of August, 2020. The gene is also associated with Muscular dystrophy-dystroglycanopathy (limb-girdle), type 3C, and referred to as LGMD2O and LGMD R15 *POMGNT1*-related in the literature (PMID: 30055862). However, the two individuals reported with the LGMD phenotype do not meet the LGMD GCEP's phenotype criteria. Therefore, the LGMD phenotype, although potentially part of the spectrum, has not been described in individuals with *POMGNT1* variants. The association myopathy caused by variation in *POMGNT1* was made using case-level and experimental data. The *POMGNT1* gene is located on chromosome 1p34.1 and encodes multiple transcript variants. The commonly referred transcript (NM_017739.3) is 2.7 kb long with 22 exons encoding a 660-amino acid protein. More than 100 pathogenic variants reported in humans with autosomal recessive myopathy caused by variation in *POMGNT1* are recorded in ClinVar, ranging from small deletions and duplications, nonsense, frameshift and splicing to missense variants. Myopathy caused by variation in *POMGNT1* encompasses a spectrum of phenotypes including severe forms with muscle-eye-brain disease, Walker-Warburg syndrome and muscular dystrophy dystroglycanopathy with intellectual disability. Patients often show an elevated serum creatine kinase and progressive muscle weakness. *POMGNT1* has been reported in association with autosomal recessive myopathy caused by variation in *POMGNT1* as early as 2001 by Yoshida et al (PMID: 11709191). OMIM entities: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 3; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 3; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 3; Retinitis pigmentosa 76. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) AND inheritance pattern AND phenotypic variability in the above mentioned disease entities. Therefore, all of the disease entities may be lumped into one disease entity, autosomal recessive myopathy caused by variation in *POMGNT1*. However, the patients with an asserted LGMD phenotype do not meet the GCEP-specific LGMD phenotype criteria and therefore are not scored. Similarly, individuals with isolated retinitis pigmentosa are not scored. Summary of Case Level Data (12 points): The association is seen in at least 7 probands in 4 publications (PMID: 11709191, 12588800, 12788071, 22419172). *POMGNT1* variants are also reported in patients with isolated Retinitis Pigmentosa without other syndromic features (PMID: 26908613). These probands are noted but not scored in this curation. More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is expected to be biallelic loss of function. Summary of Experimental Data (5.5 points): This gene-disease relationship is supported by animal models, expression studies, functional assays and rescue evidence. *POMGNT1* catalyzes the transfer of N-acetylglucosamine to O-mannose of alpha-dystroglycan and interacts with other proteins in the glycosylation pathway of alpha-dystroglycan in skeletal muscle (PMID: 16584074, 17034757, 17869517, 23454088). *POMGNT1* is expressed ubiquitously, including the retinal photoreceptors and brain, localizing to the Golgi complex and the nucleus (PMID: 27375352). Mouse models with *POMGNT1* knocked out recapitulate the human muscle-eye-brain disease phenotype (PMID: 16458488, 23454088, 19114101). In summary, the gene-disease relationship between *POMGNT1* and myopathy caused by variation in *POMGNT1* is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Limb-Girdle Muscular Dystrophy GCEP on August 11, 2020 (SOP Version 7).
Inheritance Pattern: AR
Disease ID:MONDO:0700068
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013161
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0700068
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0013161
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014929
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to POMGNT1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_017739.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 21 | 314 | 336 | ||
| missense | 5 | 44 | 439 | 14 | 502 | |
| nonsense | 27 | 29 | 1 | 57 | ||
| start loss | 2 | 2 | ||||
| frameshift | 54 | 66 | 1 | 121 | ||
| splice donor/acceptor (+/-2bp) | 7 | 69 | 10 | 86 | ||
| Total | 96 | 208 | 472 | 328 | 0 | 1104 |
Highest pathogenic variant AF is 0.00035324038
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_060209.4 | 21 | MANE Select | |
| Ensembl | ENSP00000361052.3 | 21 | MANE Select | |
| RefSeq | NP_001230695.2 | 22 | Standard | |
| RefSeq | NP_001277058.2 | 21 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Mannose type O-glycan biosynthesis - Homo sapiens (human)
- Post-translational protein modification
- Metabolism of proteins
- O-linked glycosylation
Biological Process
- protein O-linked glycosylation
- O-glycan processing
Molecular Function
- protein binding
- acetylglucosaminyltransferase activity
- manganese ion binding
- beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,3-N-acetylglucosaminyltransferase activity
Cellular Component
- Golgi membrane
- integral component of membrane
- integral component of Golgi membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000371992
- Coding exons
- 22
- Length
- 31624
- Individuals with no LoFs
- 125507
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 241
- Defined
- 125748
- p
- 0.000959
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.899 | 373 | 425 | 0.877 | 0.0000263 | 4886 |
| Missense (PolyPhen) | 112 | 137.45 | 0.81487 | 1580 | ||
| Synonymous | -0.240 | 163 | 159 | 1.02 | 0.00000899 | 1485 |
| Loss of Function | 1.32 | 36 | 45.6 | 0.789 | 0.00000274 | 487 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00026 | 0.00025 | rare |
| Latino/Admixed American | 0.00052 | 0.00052 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.00076 | 0.00076 | rare |
| Finnish | 0.0021 | 0.0021 | notable |
| European (Non-Finnish) | 0.0012 | 0.0012 | notable |
| South Asian | 0.00056 | 0.00056 | rare |
| Other | 0.00082 | 0.00081 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Participates in O-mannosyl glycosylation by catalyzing the addition of N-acetylglucosamine to O-linked mannose on glycoproteins (PubMed:11709191, PubMed:27493216). Catalyzes the synthesis of the GlcNAc(beta1-2)Man(alpha1-)O-Ser/Thr moiety on alpha-dystroglycan and other O-mannosylated proteins, providing the necessary basis for the addition of further carbohydrate moieties (PubMed:11709191, PubMed:27493216). Is specific for alpha linked terminal mannose and does not have MGAT3, MGAT4, MGAT5, MGAT7 or MGAT8 activity. {ECO:0000269|PubMed:11709191, ECO:0000269|PubMed:11742540, ECO:0000269|PubMed:26908613, ECO:0000269|PubMed:27391550, ECO:0000269|PubMed:27493216}.;
- Disease
- DISEASE: Muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A3 (MDDGA3) [MIM:253280]: An autosomal recessive disorder characterized by congenital muscular dystrophy, ocular abnormalities, cobblestone lissencephaly, and cerebellar and pontine hypoplasia. Patients present severe congenital myopia, congenital glaucoma, pallor of the optic disks, retinal hypoplasia, mental retardation, hydrocephalus, abnormal electroencephalograms, generalized muscle weakness and myoclonic jerks. Included diseases are the more severe Walker-Warburg syndrome and the slightly less severe muscle-eye-brain disease. {ECO:0000269|PubMed:11709191, ECO:0000269|PubMed:12588800, ECO:0000269|PubMed:12788071, ECO:0000269|PubMed:15207699, ECO:0000269|PubMed:15236414, ECO:0000269|PubMed:15466003, ECO:0000269|PubMed:17030669, ECO:0000269|PubMed:19067344}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muscular dystrophy-dystroglycanopathy congenital with mental retardation B3 (MDDGB3) [MIM:613151]: An autosomal recessive disorder characterized by congenital muscular dystrophy associated with mental retardation and mild structural brain abnormalities. Clinical features include mental retardation, white matter changes, cerebellar cysts, pontine hypoplasia, myopia, optic atrophy, decreased alpha-dystroglycan on muscle biopsy and increased serum creatine kinase. {ECO:0000269|PubMed:17030669, ECO:0000269|PubMed:19067344, ECO:0000269|PubMed:19299310}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muscular dystrophy-dystroglycanopathy limb-girdle C3 (MDDGC3) [MIM:613157]: A rare form of limb-girdle muscular dystrophy with normal cognition. Muscle biopsy shows dystrophic changes with variable staining for glycosylated alpha- dystroglycan. {ECO:0000269|PubMed:18195152}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Retinitis pigmentosa 76 (RP76) [MIM:617123]: A form of retinitis pigmentosa, a retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. RP76 inheritance is autosomal recessive. {ECO:0000269|PubMed:26908613, ECO:0000269|PubMed:27391550}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.301
Intolerance Scores
- LoFtool
- 0.459
- RVIS EVS
- -0.29
- RVIS percentile EVS
- 33.47
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.175
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |