DYSF p.Phe1538fs
c.4614del · rs886042578 · VCV283205
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 PP1
Curation rationale (ClinGen, verbatim)
The NM_003494.4: c.4497del p.(Phe1499LeufsTer4) variant in DYSF, which is also known as NM_001130987.2: c.4614del p.(Phe1538LeufsTer4), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 41/55 leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). In the literature, this variant has also been described as c.4870delT. This variant has been detected in at least eight unrelated individuals with limb girdle muscular dystrophy (PMID: 23243261, 12796534, 17070050, 27647186, 26088049, 17614318). Among these individuals, it was identified in a homozygous state in three patients (1.0 pts, PMID: 26088049, 17614318, 12796534) and in trans with a pathogenic variant in at least one patient (c.2643+1G>A, 1.0 pt, PMID: 23243261) (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: 27647186, 17070050). The variant was also reported to co-segregate with the disease in three affected family members from one family (PMID: 17614318) (PP1, capped with PP4_Strong). 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, PP1, 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 42 of 56 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 5.3 | GERP -1.5, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
No allele count reported in gnomAD v4.1 (AN 1,611,240). 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.Phe1538fs
- Coding
- c.4614del
- MANE Select
- NM_001130987
- dbSNP
- rs886042578
- Type
- Deletion
- Location
- chr2:71644048 (GRCh38)
- Gene constraint
- LOEUF 0.836 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 79.25 · 11 PDB
Similar variants
- 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
- DYSF p.Arg1759fs 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-phe1538fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown