The NM_003494.4: c.4497del p.(Phe1499LeufsTer4) variant in DYSF, which is also known as NM_001130987.2: c.4614del p.(Phe1538LeufsTer4), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 41/55 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). In the literature, this variant has also been described as c.4870delT. This variant has been detected in at least eight unrelated individuals with limb girdle muscular dystrophy (PMID: 23243261, 12796534, 17070050, 27647186, 26088049, 17614318). Among these individuals, it was identified in a homozygous state in three patients (1.0 pts, PMID: 26088049, 17614318, 12796534) and in trans with a pathogenic variant in at least one patient (c.2643+1G>A, 1.0 pt, PMID: 23243261) (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: 27647186, 17070050). The variant was also reported to co-segregate with the disease in three affected family members from one family (PMID: 17614318) (PP1, capped with PP4_Strong). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). 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, PM3_Strong, PP4_Strong, PP1, PM2_Supporting.