Is DYSF p.Phe299fs (c.895_896del) pathogenic?

DYSF p.Phe299fs (c.895896del) is classified Pathogenic in DYSF (ClinVar, Expert panel, 3 submitters; last evaluated 2025-05-28). Very rare (popmax 0.00223%, eas); Associated with autosomal recessive limb-girdle muscular dystrophy.

How common is DYSF p.Phe299fs (c.895_896del) in the general population?

DYSF p.Phe299fs (c.895_896del) is very rare (popmax 0.00223%, eas) (gnomAD).

DYSF p.Phe299fs

Q: What condition is associated with DYSF p.Phe299fs (c.895_896del)?

DYSF p.Phe299fs (c.895_896del) 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.895_896del · rs1337417322 · VCV639814

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 PM3_Supporting PM2_Supporting PP4_Strong

Curation rationale (ClinGen, verbatim)

The NM_003494.4: c.799_800del p.(Phe267LeufsTer5) variant in DYSF, which is also known as NM_001130987.2: c.895_896del p.(Phe299LeufsTer5), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 8/55, 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 at least seven patients with suspected LGMD or dysferlinopathy (PMID: 18853459, 25591676, 27647186, 30107846), including in a homozygous state in at least one individual with no known familial consanguinity (0.5 pts, PMID: 27647186; PM3_Supporting). At least one patient with this variant and a second presumed diagnostic DYSF variant had a clinical diagnosis of LGMD and absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 18853459; PP4_Strong). The highest minor allele frequency for this variant is 0.00002519 in the East Asian population in gnomAD v4.1.0 (1/39700 exome 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; 05/28/2025): PVS1, PM3_Supporting, 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 9 of 56
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.9	GERP 0.61, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

Overall 6.19e-05% 1/1,614,218 alleles · very rare exomes 1/1,461,874 · genomes 0/152,344 · joint denominator

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.Phe299fs
Coding: c.895_896del
MANE Select: NM_001130987
dbSNP: rs1337417322
Type: Deletion
Location: chr2:71516184 (GRCh38)
Gene constraint: LOEUF 0.836 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25 · 11 PDB
Residue 299: a β-strand; a UniProt-annotated variant site (in mmd1); a UniProt-annotated variant site (in lgmdr2 and proximodistal myopathy); the c2 2 domain

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

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-phe299fs (accessed [today's date]).

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