DYSF

Chr 2AR

dysferlin

Also known as: FER1L1, LGMD2B, LGMDR2, MMD1

NCBI Gene: 8291ENSG00000135636UniProt: O75923

The protein encoded by this gene belongs to the ferlin family and is a skeletal muscle protein found associated with the sarcolemma. It is involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. In addition, the protein encoded by this gene binds caveolin-3, a skeletal muscle membrane protein which is important in the formation of caveolae. Specific mutations in this gene have been shown to cause autosomal recessive limb girdle muscular dystrophy type 2B (LGMD2B) as well as Miyoshi myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2008]

Primary Disease Associations & Inheritance

Miyoshi muscular dystrophy 1MIM #254130
AR
Muscular dystrophy, limb-girdle, autosomal recessive 2MIM #253601
AR
Myopathy, distal, with anterior tibial onsetMIM #606768
AR
UniProtDistal myopathy with anterior tibial onset
4614
ClinVar variants
82
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— DYSF
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
82 Pathogenic / Likely Pathogenic· 198 VUS of 4614 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.73LOEUF
pLI 0.000
Z-score 4.01
OE 0.60 (0.50–0.73)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.04Z-score
OE missense 1.00 (0.95–1.04)
1232 obs / 1235.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.60 (0.50–0.73)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.00 (0.95–1.04)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.11
0≤1.21.6
LoF obs/exp: 72 / 119.3Missense obs/exp: 1232 / 1235.8Syn Z: -1.86

ClinVar Variant Classifications

4614 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43
Likely Pathogenic39
VUS198
Likely Benign181
Benign3
43
Pathogenic
39
Likely Pathogenic
198
VUS
181
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
28
2
13
0
43
Likely Pathogenic
32
5
2
0
39
VUS
1
158
18
21
198
Likely Benign
0
5
102
74
181
Benign
0
0
3
0
3
Total6117013895464

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
DYSFERLIN; DYSF
MIM #603009 · *

Miyoshi muscular dystrophy 1

MIM #254130

Molecular basis of disorder known

Autosomal recessive

Muscular dystrophy, limb-girdle, autosomal recessive 2

MIM #253601

Molecular basis of disorder known

Autosomal recessive

Myopathy, distal, with anterior tibial onset

MIM #606768

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.
Töpf A et al.·Genet Med
2020Cohort
Panorama of the distal myopathies.
Savarese M et al.·Acta Myol
2020Review
Molecular landscape of DYSF mutations in dysferlinopathy: From a Chinese multicenter analysis to a worldwide perspective.
Zhong H et al.·Hum Mutat
2021
Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients.
Fichna JP et al.·Hum Genomics
2018Cohort
Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients.
Ten Dam L et al.·Clin Genet
2019Cohort
Dysferlin Gene Mutation Spectrum in a Large Cohort of Chinese Patients with Dysferlinopathy.
Jin SQ et al.·Chin Med J (Engl)
2016Cohort
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
Dysferlinopathies: Clinical and genetic variability.
Ivanova A et al.·Clin Genet
2022Review
Clinical, Histopathologic, and Genetic Features of Patients With Myofibrillary and Distal Myopathies: Experience From the Italian Network.
Bortolani S et al.·Neurology
2024Cohort
Functions of Vertebrate Ferlins.
Bulankina AV et al.·Cells
2020Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
DysferlinopathyMiyoshi MyopathyLGMDR2

Clinical, Immunological, Morphological and Genetic Characteristics of Patients With Dysferlinopathy (LGMD R2) in the RF

ENROLLING BY INVITATION
NCT04824040Artgen BiotechStarted 2020-01-15

External Resources

Links to major genomics databases and tools