Submission Details

SGCG was first reported in relation to autosomal recessive limb-girdle muscular dystrophy in 1995 (Noguchi et al., PMID: 7481775). The original disease nomenclature used was LGMD2C, which was later transitioned to LGMDR5. At least 75 variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, etc) have been reported in humans according to HGMD. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least eight probands in four publications (PMIDs: 8923014, 7481775, 8968757, 27708273). Variants in this gene segregated with disease in over fifty additional family members. SGCG has many recognized founder variants passed down through smaller isolated populations, some being the North African variant 525delT and the Roma variant among others. SGCG also is prone to large exonic deletions, most prominently the deletion of Exon 6 but others have previously been reported. Many more probands and evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence has been reached. The mechanism for disease is protein loss of function, with loss of gamma-sarcoglycan resulting in a corresponding loss of the other sarcoglycans and destabilization of the Dystrophin-Associated Protein Complex from the sarcolemma. This gene-disease association is supported by animal models, expression studies, functional assays, and a functional rescue. Protein interactions and having the same biochemical function as the other sarcoglycans associated with LGMD provides strong evidence, as well as the primary expression in skeletal muscle. Mouse models of disrupted SGCG function consistently recapitulate the human LGMD phenotype. Additionally, the introduction of full length SGCG cDNA via a viral construct rescued the disease phenotype observed in the mouse. In summary, SGCG is definitively associated with autosomal recessive limb-girdle muscular dystrophy. 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 April 14, 2020 (SOP Version 7).

This gene curation was re-approved and published on 11/14/24 by the Muscular Dystrophies and Myopathies GCEP to reflect the change in the panel's name from LGMD GCEP to MDM GCEP. As part of this process, the genetic evidence was re-scored in accordance with SOP version 11.