DYSF p.Asp320fs
c.959dup · rs1559057405 · VCV2674961
ClinGen expert panel — Limb Girdle Muscular Dystrophy VCEP
Pathogenic for autosomal recessive limb-girdle muscular dystrophy. Applied ACMG criteria (verbatim):
PVS1 PM3_Supporting PM2_Supporting
Curation rationale (ClinGen, verbatim)
The NM_003494.4: c.863dup p.(Asp288GlufsTer40) variant in DYSF, which is also known as NM_001130987.2: c.959dup p.(Asp320GlufsTer40), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least two individuals with dysferlinopathy (PMID: 36983702, 33715265, 14673575; LOVD DYSF_000186), including in unknown phase with a pathogenic variant (NM_003494.4: c.3031+2T>C, 0.5 pts, PMID: 36983702; PM3_Supporting). The filtering allele frequency of this variant in gnomAD v4.1.0 exomes is 0.000008232 (the upper threshold of the 95% CI of 4/1111996 European (non-Finnish) chromosomes), which is lower than the ClinGen LGMD VCEP threshold (<0.0001) for PM2_Supporting, and therefore meets this criterion (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; 07/29/2025): PVS1, PM3_Supporting, 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 10 of 56 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 9.8 | GERP 1.9, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- DYSF
- Protein
- p.Asp320fs
- Coding
- c.959dup
- MANE Select
- NM_001130987
- dbSNP
- rs1559057405
- Type
- Duplication
- Location
- chr2:71516995 (GRCh38)
- Gene constraint
- LOEUF 0.836 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 79.25 · 11 PDB
- Residue 320
- a β-strand; the c2 2 domain
Disease context
autosomal recessive limb-girdle muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: autosomal recessive limb-girdle muscular dystrophy type 2Bdistal myopathy with anterior tibial onsetneuromuscular disease caused by qualitative or quantitative defects of dysferlinMiyoshi muscular dystrophy 1
Similar variants
- DYSF p.Asp320Val Pathogenic ★★★ same residue
- DYSF p.Asp320= Likely benign ★ same residue
- 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.Asp497fs Pathogenic ★★★ same condition
- DYSF p.Glu2033fs 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-asp320fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown