DYSF p.Asp1255fs
c.3762del · rs758107024 · VCV813985
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 PM3_Strong
Curation rationale (ClinGen, verbatim)
The NM_003494.4: c.3708delA p.(Asp1237ThrfsTer24) variant in DYSF, which is also known as NM_001130987.2: c.3762del p.(Asp1255ThrfsTer24), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 34/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least three unrelated individuals with limb girdle muscular dystrophy, including in a homozygous state in two patients (1.0 pts, PMID: 25046369, 30919934) and in trans with a pathogenic variant in at least one patient (c.1662C>T p.(Arg555Trp), 1.0 pt, PMID: 19015158) (PM3_Strong). At least one patient with this variant displayed progressive limb-girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 19015158). This variant is absent from gnomAD v2.1.1 and v3.1.2 (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; 01/08/2025): PVS1, PM3_Strong, 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 34 of 56 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 5.9 | GERP 0.84, 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.Asp1255fs
- Coding
- c.3762del
- MANE Select
- NM_001130987
- dbSNP
- rs758107024
- Type
- Deletion
- Location
- chr2:71600707 (GRCh38)
- Gene constraint
- LOEUF 0.836 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 79.25 · 11 PDB
- Residue 1255
- an α-helix; the c2 4 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 2Bneuromuscular disease caused by qualitative or quantitative defects of dysferlin
Similar variants
- DYSF p.Asp1255= Likely benign ★ same residue
- DYSF c.240-159_345+1237del Pathogenic ★★★ same condition
- DYSF c.345+1del Pathogenic ★★★ same condition
- DYSF c.3756+905_3897+151del Pathogenic ★★★ same condition
- DYSF c.5885-51_6063+50del Pathogenic ★★★ same condition
- DYSF c.92-1496_239+950del Pathogenic ★★★ same condition
- DYSF c.951+1del Pathogenic ★★★ same condition
- DYSF p.Ala927Leufs 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-asp1255fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown