DYSF p.His1896Arg

The NM_003494.4: c.5570A>G variant in DYSF, which is also known as NM_001130987.2: c.5687A>G p.(His1896Arg), is a missense variant predicted to cause the substitution of histidine with arginine at amino acid 1857, p.(His1857Arg). This variant has been identified in at least five unrelated individuals with features consistent with LGMD (PMID: 30564623, 36319958, 11468312, 9731526; ClinVar SCV004292580.2 internal data communication). These reports include one homozygous patient without reported consanguinity (0.5 pts, ClinVar SCV004292580.2 internal data communication) and three patients where it was reported in unconfirmed phase with a pathogenic variant (NM_003494.4: c.2779del (p.Ala927LeufsTer21), 0.5 pts, PMID: 30564623, LOVD Individual #00222471; c.156G>A p.(Trp52Ter), 0.5 pts, PMID: 36319958; c.1129C>T p.(Arg377Ter), 0.5 pts, ClinVar SCV004292580.2 internal data communication) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic DYSF variant displayed both progressive limb girdle muscle weakness and strongly reduced dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-related LGMD (PMID: 36319958; PP4_Strong). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency is 0.000006751 in gnomAD v4.1.0 (3/1180062 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (<0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.929, which is above the LGMD 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 Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (specifications v2.0.0; 04/01/2026): PM3_Strong, PP4_Strong, PM2_Supporting, PP3.