DYSF p.Arg1056Pro

The NM_003494.4: c.3113G>C variant in DYSF, which is also known as NM_001130987.2: c.3167G>C p.(Arg1056Pro), is a missense variant predicted to cause substitution of arginine by proline at amino acid 1038, p.(Arg1038Pro). This variant has been reported in at least one individual with features consistent with LGMD, where it was confirmed in trans with a likely pathogenic or pathogenic variant (NM_003494.4: c.4756C>T p.(Arg1586Ter), 1.0 pt, PMID: 36983702, 33610434) (PM3). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD (Miyoshi myopathy) and absent dysferlin protein expression in both skeletal muscle and blood monocytes, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 33610434; 36983702). The filtering allele frequency of this variant is 0.000014124 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 9/1111952 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001), meeting this criterion (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg1038Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). In addition, the computational predictor REVEL gives a score of 0.89, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). Another missense variant at the same codon, c.3113G>A p.(Arg1038Gln), has been classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the LGMD VCEP (PM5). 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; 04/16/2025): PM3, PP4_Strong, PM2_Supporting, PS3_Moderate, PP3, PM5.