The NM_003494.4: c.855+1del variant in DYSF, which is also known as NM_001130987.2: c.951+1del, occurs within the canonical splice donor site of intron 8. It is predicted to cause skipping of biologically relevant exon 8/55, resulting in an in-frame deletion of 21 amino acids (PVS1_Moderate). RNAseq data has confirmed that this variant results in in aberrant splicing, suggesting use of an alternative acceptor site that deletes the first basepair of DYSF exon 9 and leads to a frameshift and premature truncation p.(Val286TrpfsTer2) (PMID: 36983702). This variant has been detected in at least 12 individuals with limb girdle muscular dystrophy (PMID: 20544924, 17828519, 18853459, 36983702). Of those individuals, at least two were compound heterozygous for the variant and a pathogenic variant (c.3504dup p.(Lys1169GlnfsTer6), 1.0 pt, PMID: 20544924; c.3126G>A p.(Trp1024Ter): 1.0 pt, PMID: 18853459), and at least one was homozygous (0.25 pts, PMID: 18853459) (PM3_Strong). At least one patient with this variant displayed progressive limb-girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 18853459, 36983702). The variant was also reported to co-segregate with the disease in two affected family members from two families (PMID: 18853459) (PP1, capped with PP4_Strong). The filtering allele frequency of the variant is 0.0009441 for Admixed American genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 8/15286), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PVS1_Moderate, PM3_Strong, PP4_Strong, PP1.