POMGNT2

Inheritance Pattern: AR

Disease ID:MONDO:0013904

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013904

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0013904

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0013904

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0700069

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0000171

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0700069

Submitter: ClinGen

*POMGNT2* was first reported in relation to myopathy caused by variation in *POMGNT2* in ​2012 (Manzini et al., PMID 22958903)​​. At least seven unique variants (including missense, nonsense, and frameshift variants) have been reported in humans. Evidence ​supporting this gene-disease relationship includes​ case-level genetic data and experimental data linking *POMGNT2* loss of function to myopathy caused by variation in *POMGNT2*. Lumping and Splitting Considerations: OMIM entities: autosomal recessive congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A8 (MIM 614830); autosomal recessive limb-girdle muscular dystrophy-dystroglycanopathy type C8 (MIM 618135) Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s), inheritance pattern, or phenotypic variability in the above mentioned disease entities. Therefore, all of the disease entities have been lumped into one disease entity: autosomal recessive myopathy caused by variation in *POMGNT2* . Lumping decision approved on July 1, 2020. Summary of Case-Level Data (8.5 points): Variants in this gene have been reported in at least nine probands with myopathy caused by variation in *POMGNT2* in five publications (PMID 22958903, PMID 27066570, PMID 25558065, PMID 26112015, PMID 26436962). The phenotypes described in these individuals range widely in severity and age of onset, with some patients exhibiting Walker-Warburg syndrome surviving only days or weeks beyond birth, while later onset has been reported in patients with milder limb-girdle muscular dystrophy with or without intellectual disability. Summary of Experimental Data (6 points): This gene-disease relationship is supported by biochemical function studies, in vitro functional assays, and animal models. The *POMGNT2* protein is involved in the catalysis of the second step of O-mannosyl glycosylation in the mucin-like domain of α-dystroglycan. Defects in the glycosylation of α-dystroglycan disrupt dystroglycan binding to laminin-G domain-containing extracellular proteins in muscle and brain and are well-known to lead to dystroglycanopathies (PMID 23929950). Loss of *POMGNT2* in cultured cells and zebrafish and mouse models leads to hallmark muscular dystrophy dystroglycanopathy biochemical and phenotypic features, some of which have been mitigated by rescue (PMID 27066570, PMID 22958903, PMID 24256719). In summary, *POMGNT2* is definitively associated with myopathy caused by variation in *POMGNT2*. 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 Neuromuscular Working Group on September 8, 2020 (SOP Version 7).