DYSF

Chr 2AR

dysferlin

Also known as: FER1L1, LGMD2B, LGMDR2, MMD1

NCBI Gene: 8291ENSG00000135636UniProt: O75923OMIM: 603009

The encoded protein is a skeletal muscle sarcolemma protein that mediates calcium-dependent membrane fusion events for muscle membrane repair and regeneration, and binds caveolin-3 for caveolae formation. Mutations cause autosomal recessive limb-girdle muscular dystrophy type 2B, Miyoshi muscular dystrophy, and distal myopathy with anterior tibial onset through a gain-of-function mechanism. These conditions present as progressive muscle weakness affecting different muscle groups depending on the specific phenotype.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
MultiplemechanismARLOEUF 0.733 OMIM phenotypes
VCEP Guidelines: Limb Girdle Muscular DystrophyReleased
ClinGen Panel
Clinical Summary— DYSF
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Gene-Disease Validity (ClinGen)
autosomal recessive limb-girdle muscular dystrophy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
60 unique Pathogenic / Likely Pathogenic· 26 VUS of 300 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.73LOEUF
pLI 0.000
Z-score 4.01
OE 0.60 (0.50–0.73)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.04Z-score
OE missense 1.00 (0.95–1.04)
1232 obs / 1235.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.60 (0.50–0.73)
0≤0.351.4
Missense OE1.00 (0.95–1.04)
0≤0.61.4
Synonymous OE1.11
0≤1.21.6
LoF obs/exp: 72 / 119.3Missense obs/exp: 1232 / 1235.8Syn Z: -1.86
DN
0.6647th %ile
GOF
0.72top 25%
LOF
0.3452th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

300 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic41
VUS26
Likely Benign210
Benign4
19
Pathogenic
41
Likely Pathogenic
26
VUS
210
Likely Benign
4
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
17
2
0
0
19
Likely Pathogenic
30
9
2
0
41
VUS
1
20
2
3
26
Likely Benign
0
4
128
78
210
Benign
0
0
4
0
4
Total483513681300

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

DYSF · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients