Is DYSF p.Phe1713fs (c.5139del) pathogenic?

DYSF p.Phe1713fs (c.5139del) is classified Pathogenic in DYSF (ClinVar, Expert panel, 7 submitters; last evaluated 2025-07-29). Very rare (popmax 0.000254%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is DYSF p.Phe1713fs (c.5139del) in the general population?

DYSF p.Phe1713fs (c.5139del) is very rare (popmax 0.000254%, nfe) (gnomAD).

DYSF p.Phe1713fs

Q: What condition is associated with DYSF p.Phe1713fs (c.5139del)?

DYSF p.Phe1713fs (c.5139del) is associated with autosomal recessive limb-girdle muscular dystrophy, autosomal recessive limb-girdle muscular dystrophy type 2B, neuromuscular disease caused by qualitative or quantitative defects of dysferlin (ClinVar).

c.5139del · rs1057519132 · VCV374503

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

autosomal recessive limb-girdle muscular dystrophy

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.5022del p.(Phe1674LeufsTer48) variant in DYSF, which is also known as NM_001130987.2: c.5139del p.(Phe1713LeufsTer48), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 46/55, 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 three individuals with features consistent with limb girdle muscular dystrophy (PMID: 14673575, 36983702, 23406536), including confirmed in trans with a likely pathogenic or pathogenic variant in two patients (NM_003494.4: c.4756C>T p.(Arg1586Ter), 1.0 pts, PMID: 14673575; NM_003494.4: c.6196G>A p.(Ala2066Thr), 1.0 pt, PMID: 36983702) (PM3_Strong). At least one patient with this variant had a clinical suspicion of LGMD and absent dysferlin protein expression in skeletal muscle, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 14673575). The filtering allele frequency of this variant is 0.000006973 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/1112010 European (non-Finnish) chromosomes) , which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (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_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 46 of 56
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3	GERP 0.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,044 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,892 alleles · very rare

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.Phe1713fs
Coding: c.5139del
MANE Select: NM_001130987
dbSNP: rs1057519132
Type: Deletion
Location: chr2:71664401 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 1713: an α-helix

Full DYSF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive limb-girdle muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive limb-girdle muscular dystrophy type 2B neuromuscular disease caused by qualitative or quantitative defects of dysferlin Miyoshi muscular dystrophy 1

Similar variants

DYSF p.Phe1713Leu Uncertain significance ★★ ⚠ same residue
DYSF p.Phe1713Ser Uncertain significance ★★ ⚠ 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

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-phe1713fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown