DYSF c.3085+2T>C

The NM_003494.4: c.3031+2T>C variant in DYSF, which is also known as NM_001130987.2: c.3085+2T>C, occurs within the canonical splice donor site (+/- 1,2) of intron 28. SpliceAI gives a delta score of 0.92 for loss of the canonical donor. RNAseq analysis has demonstrated that this variant causes skipping of exon 28, resulting in a frameshift and premature truncation, p.Asn976AlafsTer46 (PMID: 36983702; PVS1_RNA). This variant has been reported in at least six patients with clinical features consistent with LGMD, including in a homozygous state (0.5 pts) and confirmed in trans with a pathogenic variant (NM_003494.4: c.855+1del, 1.0 pt) (PMID: 26444858, 36983702, 18853459; PM3). At least one individual with this variant and a second DYSF variant had a clinical phenotype considered consistent with LGMD (PMID: 18853459; PP4). In addition, this variant has been shown to co-segregate with autosomal recessive LGMD in at least four family members from three families (PMID: 26444858, 18853459; PP1_Strong). Haplotype analysis of three seemingly unrelated families from Central Switzerland confirmed a founder effect of this variant in that region. The highest population allele frequency of this variant is in gnomAD v4.1.0 is 8.476e-7 (1/1179858 European (non-Finnish) alleles), which is less than the LGMD VCEP threshold for PM2_Supporting (0.0001), meeting this criterion (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; 07/29/2025): PVS1_RNA, PM3, PP4, PP1_Strong, PM2_Supporting.