DYSF p.Lys459fs
c.1374dup · rs2545508940 · VCV2116162
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting PP4_Strong
Curation rationale (ClinGen, verbatim)
The NM_003494.4: c.1278dup p.(Lys427GlufsTer47) variant in DYSF, which is also known as NM_001130987.2: c.1374dup p.(Lys459GlufsTer47), is a duplication expected to cause a frameshift, premature stop codon, and nonsense-mediated decay in a gene for which loss of function is an established mechanism of disease (PVS1). This variant has been identified in one individual with progressive muscle weakness, elevated serum creatine kinase, and suspected Miyoshi myopathy as well as absent dysferlin expression by blood monocyte assay, where it was identified in unconfirmed phase with a second presumed diagnostic DYSF variant (ClinVar SCV002975439.1, Jain Foundation Dysferlin Registry internal data communication; PP4_Strong, PM3_Supporting not met). It is absent from gnomAD v.4.1.0, meeting the criteria for PM2_Supporting. In summary, this variant meets 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; 04/30/2026): PVS1, PP4_Strong, PM2_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 14 of 56 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 7.4 | GERP 2.1, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.
Variant & gene context
- Gene
- DYSF
- Protein
- p.Lys459fs
- Coding
- c.1374dup
- MANE Select
- NM_001130987
- dbSNP
- rs2545508940
- Type
- Duplication
- Location
- chr2:71528391 (GRCh38)
- Gene constraint
- LOEUF 0.836 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 79.25 · 11 PDB
- Residue 459
- a β-strand; the c2 3 domain
Similar variants
- DYSF c.1267_1276+4dup Pathogenic ★★★ same condition
- DYSF c.1274_1276+4dup Likely pathogenic ★★★ same condition
- DYSF c.1493+2dup Pathogenic ★★★ same condition
- DYSF p.Asn44fs Pathogenic ★★★ same condition
- DYSF p.Asp320fs Pathogenic ★★★ same condition
- DYSF p.Asp497fs Pathogenic ★★★ same condition
- DYSF p.Glu2033fs Pathogenic ★★★ same condition
- DYSF p.Ile1036Hisfs Pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/dysf-p-lys459fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown