DYSF p.Ser1372del

The NM_003494.4: c.4060_4062del p.(Ser1354del) variant in DYSF, which is also known as NM_001130987.2: c.4114_4116del p.(Ser1372del), is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region (PM4). This variant has been reported in at least eight individuals with features consistent with LGMD (PMID: 33250842, 30827497, 36983702, 30564623; LOVD DYSF_000416). At least one of these patients was reported to carry the c.4060_4062del p.(Ser1354del) variant in trans with NM_003494.4: c.4439A>C p.(Lys1480Thr), which is classified as likely pathogenic by the LGMD VCEP (1.0 pt, LOVD Individuals #00215628, #00215714) (PM3). The c.4060_4062del p.(Ser1354del) variant has also been reported in a homozygous state in one patient with presumed familial consanguinity from the Indian subcontinent (PMID: 33250842). However, among the reported cases, at least six, all of Indian origin, were homozygous for both c.4060_4062del p.(Ser1354del) and c.4439A>C p.(Lys1480Thr), indicating these two variants occur in cis (BP2; PMID: 30564623, 36983702; LOVD Individuals #00219454, #00222227; Jain Foundation Dysferlin Registry internal data communication). The highest minor allele frequency for this variant is 0.00002319 in the South Asian population of gnomAD v4.1.0 exomes (2/86250 chromosomes), which is lower than the LGMD VCEP threshold (0.0001) (PM2_Supporting). In summary, there is currently insufficient evidence to determine whether this variant, when identified without NM_003494.4: c.4439A>C p.(Lys1480Thr) as part of a complex allele, is benign or pathogenic. It is therefore classified as a variant of uncertain significance 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; 04/22/2025): PM4, PM3, BP2, PM2_Supporting.