ClinVar

Description

Variant summary: SGCB c.-10_22dup32 is located in the untranslated mRNA region upstream and the coding region including the initiation codon.The variant was absent in 37246 control chromosomes (gnomAD v2), however, it is found in 9/150846 controls in gnomAD v3. c.-10_22dup32 has been reported in the literature in multiple individuals affected with mild Limb-Girdle Muscular Dystrophy in homozygous state (Boito_2003, Semplicini_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This variant is predicted to result in p.Ala8Glyfs*22 if the first initiation codon is utilized for translation. However, biochemical data of residual sarcoglycan expression in skeletal muscle and mild phenotype in variant carriers suggest that the second initiation codon in the mutant gene may also be utilized, which results in a normal protein (Semplicini_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Although this variant has been found in mutliple patients, due to lack of functional evidence, the variant was classified as likely pathogenic.