DYSF p.Gln253His

The NM_003494.4: c.663G>C variant in DYSF, which is also known as NM_001130987.2: c.759G>C p.(Gln253His), is a missense variant predicted to cause substitution of glutamine by histidine at amino acid 221, p.(Gln221His). This variant has been reported in at least four unrelated individuals with features consistent with LGMD (PMID: 35047756, 36580222; ClinVar SCV000953073.7 internal data communication), including in unconfirmed phase with a pathogenic variant in two patients (NM_003494.4: c.1020C>A p.(Ser340Arg), 0.5 pts, PMID: 35047756; c.5570A>G p.(His1857Arg), 0.5 pts, ClinVar SCV000953073.7 internal data communication) and in a homozygous state in one patient with known familial consanguinity (0.25 pts, PMID: 36580222) (PM3). At least one individual with this variant and a second pathogenic DYSF variant displayed progressive limb girdle muscle weakness or had a clinical suspicion of LGMD (PMID: 35047756; PP4). This variant has been observed in a heterozygous state with a second presumed diagnostic DYSF variant in one affected family member, but phase was not confirmed (ClinVar SCV000953073.7 internal data communication; PP1 not met). The highest frequency of this variant in a non-bottlenecked genetic ancestry group in gnomAD v4.1.0 is 0.000000047 (1/1180028 European (non-Finnish) chromosomes), which is lower than the LGMD VCEP threshold (<0.0001) (PM2_Supporting). This variant is located within the splice donor region of exon 6, affecting the last nucleotide of the exon. SpliceAI gives a delta score of 0.97 for loss of the canonical donor and of 0.72 for strengthening of a cryptic donor located at +72, suggesting altered splicing may occur. In addition, the computational predictor REVEL gives a score of 0.802, which is above the LGMD VCEP threshold of ≥0.70 (PP3). Another nucleotide change affecting the same splice motif and with the same predicted splice effect, NM_003494.4: c.663+1G>C, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PS1_Moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (specifications v2.0.0; 04/28/2026): PM3, PP4, PM2_Supporting, PP3, PS1_Moderate.