Evidence indicating a relationship between variants in SGCA and autosomal recessive muscular dystrophy was reported by Roberds et al., 1994 (PMID: 8069911), in which variants in SGCA were found to segregate in a large French family that showed linkage analysis implicating chromosome 17 with limb girdle muscular dystrophy (Romero et al., 1994; PMID: 7987694). Limb girdle muscular dystrophy (LGMD) is characterized by progressive muscle weakness of proximal limb with age, which can lead to difficulty walking or complete loss of ambulation requiring wheel chair use. Other phenotypic features associated include scapular winging, calf pseudo hypertrophy, contractors, and in some cases cardiomyopathy (PMID: 22303798, 19781108 ). Numerous variants have been reported, in both ClinVar and in LOVD (https://databases.lovd.nl/shared/genes/SGCA). Further, the p.Arg77Cys variant is a known founder variant and has been estimated to account for ~30% of autosomal recessive LGMD associated with SGCA (PMID: 9192266, 15736300, 8528203). Evidence supporting this gene-disease relationship includes case-level data, segregation data, functional data, and model organisms. This gene-disease relationship has been studied for more than 20 years, therefore a significant amount of case-level data, segregation data, and experimental data is available, however the maximum score for genetic evidence (12 points) and experimental evidence (6 points) has been reached. The mechanism for the gene-disease relationship is protein loss of function, as SGCA encodes alpha-sarcoglycan, an essential component of the dystrophin-glycoprotein complex (PMID: 19781108) present in striated muscle costameres which function in muscle contraction. In summary, SGCA is definitively associated with autosomal recessive limb girdle muscular dystrophy (MONDO:0015152). 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 02/07/20 (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.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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