Submission Details

The relationship between SGCB and limb girdle muscular dystrophy (LGMD; also known as LGMD 2E and LGMD R4) inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of January, 2020. This association was made using case-level and experimental data. The SGCB gene is located on chromosome 4q12, 4.4 kb long with 6 exons encoding a 318-amino acid protein. At least 15 pathogenic variants reported in humans with autosomal recessive LGMD are recorded in ClinVar, ranging from small deletions and duplications, nonsense, frameshift and splicing to missense variants. Limb girdle muscular dystrophy is characterized by progressive muscle weakness, mostly in the proximal muscles and affecting the pelvic and shoulder girdle, accompanied by an elevated serum creatine kinase and the loss of the ability to walk before the age of 20. Cardiomyopathy is also an accompanying feature in some individuals. SGCB has been reported in association with autosomal recessive LGMD as early as 1995 by Lim et al and Bonnemann et al (PMIDs: 7581449, 7581448). Summary of Case Level Data (12 points): The association is seen in at least 13 probands in 7 publications (PMID: 30919934, 25862795, 8968749, 28687063, 10662809, 7581449, 7581448). Variants in this gene segregated with disease in 6 additional family members. At least two founder variants have been reported in this gene in the Southern Indiana Amish (Thr151Arg) and the Dutch (Ser114Phe) populations. 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 has been reported 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. SGCB encodes β-sarcoglycan, a subunit of the sarcoglycan complex, which is a component of the dystrophin-glycoprotein complex stabilizing the sarcolemma (PMID: 7581448). β-sarcoglycan is ubiquitously expressed but is most strongly expressed in the striated muscle, heart and smooth muscle (PMID: 7581448). β-sarcoglycan interacts with δ-Sarcoglycan, encoded by SGCD, to form the core and initiate assembly of the sarcoglycan complex (PMID: 9864373). Sgcb-null mice recapitulate the human phenotype, displaying elevated creatine kinase levels and histopathological features of muscular dystrophy and cardiomyopathy (PMID: 10678176, 10441321). AAV-mediated delivery of the human SGCB transgene resulted in lowering of creatine kinase levels, partial correction of cardiac functional deficits and recovery of the diaphragm muscle (PMID: 28284983). In summary, the SGCB-autosomal recessive limb-girdle muscular dystrophy gene-disease relationship 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 February 11, 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.