DYSF p.Asn44fs

The NM_003494.4: c.125dup p.(Asn43GlufsTer6) variant in DYSF, which is also known as NM_001130987.2: c.128dup (p.Asn44GlufsTer6), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in one individual with a diagnosis of Miyoshi myopathy, where it was identified in unknown phase with a second DYSF variant that can be classified as likely pathogenic independent of its observation in this patient (NM_003494.4: c.5159del p.(Arg1720LeufsTer2), 0.25 pts, PMID: 36983702; PM3_Supporting not met). This patient showed both progressive limb girdle muscle weakness and disease range dysferlin expression in blood monocytes (PMID: 36983702, Jain Foundation Registry internal data communication; PP4_Strong). The affected sibling of this patient carried the same two DYSF variants and also had disease range dysferlin protein expression in blood monocytes, but segregation could not be scored since the phase of the variants was not confirmed (PP1 not met). This variant is absent from gnomAD v2.1.1 and v4.1.0, although a different variant resulting in the same frameshift is present on one allele (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; 02/25/2025): PVS1, PP4_Strong, PM2_Supporting.