ClinVar Genomic variation as it relates to human health

Variant summary: The variant identified by MLPA or other technology involves the deletion of exon 1 that contains the canonical translation initiation codon of the DYSF gene. The exact breakpoint at the 5' end of this variant is unknown and therefore this deletion might extend upstream of the assayed region of the gene, affecting the promoter (including essential regulatory elements). A presumed nomenclature of c.(?_-377)_(88+1_89-1)del has been designated for the purposes of this classification. This deletion is expected to result in an absent or shortened protein product, a known mechanism of disease. The first potential downstream in-frame start codon (ATG) is located in exon 3 at Met75, however several truncations and missense variants have been reported 5' of this position in affected individuals (HGMD), indicating a functional importance for this protein region. The variant was absent in 21694 control chromosomes in the gnomAD database (structural variants dataset). To our knowledge, no occurrence of c.(?_-377)_(88+1_89-1)del in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.