DYSF p.Pro809Arg

The NM_003494.4: c.2372C>G variant in DYSF, which is also known as NM_001130987.2: c.2426C>G p.(Pro809Arg), is a missense variant predicted to cause substitution of proline by arginine at amino acid position 809, p.(Pro791Arg). This variant has been detected in a homozygous state in at least five seemingly unrelated individuals with features consistent with limb girdle muscular dystrophy (1 pt; PMID: 30564623, 16996541, 10196377; PM3). It has also been reported in unconfirmed phase with a VUS in an individual with undetectable dysferlin protein expression (Jain Foundation Dysferlin Registry internal data communication). At least one patient with this variant in a homozygous state displayed progressive limb girdle muscle weakness and significantly reduced DYSF protein expression, which is highly specific for DYSF-related LGMD (PP4_Strong; PMID: 16996541, 10196377). This variant was also shown to co-segregate with autosomal recessive LGMD in at least 10 affected family members from three Canadian Indigenous families sharing the same haplotype, suggesting it is a founder variant in that population (PMID: 10196377; PP1_Supporting, capped with PP4_Strong). This variant is absent from gnomAD v4.1.0. (PM2_Supporting). The computational predictor REVEL gives a score of 0.902, which meets the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). 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 (LGMD VCEP specifications version 2.0.0; 04/30/2026): PM3, PP4_Strong, PP1, PM2_Supporting, PP3.