# NM_001130987.2(DYSF):c.895_896del (p.Phe299fs)

https://sugi.bio/variant/dysf-p-phe299fs

## Summary

**DYSF p.Phe299fs (c.895_896del)** 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.

**At a glance:** Pathogenic · review: Expert panel · rsID rs1337417322 · 3 submitters · 3 linked conditions · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the DYSF gene that is considered disease-causing, submitted by 3 submitters, and is linked to autosomal recessive limb-girdle muscular dystrophy.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019825/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DYSF](https://sugi.bio/atlas/gene/DYSF/) |
| Protein change (HGVS p.) | p.Phe299fs |
| Coding change (HGVS c.) | c.895_896del |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| dbSNP | [rs1337417322](https://www.ncbi.nlm.nih.gov/snp/rs1337417322/) |
| Variant type | Deletion |
| Location | chr2:71516184-71516185 (GRCh38) |
| ClinVar | [VCV639814](https://www.ncbi.nlm.nih.gov/clinvar/variation/639814/) |

**All HGVS expressions:** `LRG_845:g.67564_67565del`, `LRG_845t1:c.799_800del`, `LRG_845t2:c.895_896del`, `NC_000002.11:g.71743316_71743317del`, `NC_000002.12:g.71516186_71516187del`, `NG_008694.1:g.67564_67565del`, `NM_001130455.2:c.802_803del`, `NM_001130976.2:c.799_800del`, `NM_001130977.2:c.799_800del`, `NM_001130978.2:c.799_800del`, `NM_001130979.2:c.892_893del`, `NM_001130980.2:c.892_893del`, `NM_001130981.2:c.892_893del`, `NM_001130982.2:c.895_896del`, `NM_001130983.2:c.802_803del`, `NM_001130984.2:c.802_803del`, `NM_001130985.2:c.895_896del`, `NM_001130986.2:c.802_803del`, `NM_001130987.2:c.895_896del`, `NM_003494.4:c.799_800del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 5.89, GERP 0.606, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.836, pLI 3.6575e-52. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 56**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,876 in the highest group · 1/1,614,218 alleles overall — very rare (popmax 0.00223%, eas).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DYSF** population constraint: LOEUF 0.836, pLI 3.6575e-52, missense-Z 1.3979. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **autosomal recessive limb-girdle muscular dystrophy** — Definitive (AR)

## Protein context {#protein}

Residue **299** lies in a β-strand; a UniProt-annotated variant site (in mmd1); a UniProt-annotated variant site (in lgmdr2 and proximodistal myopathy); the c2 2 domain.

AlphaFold model confidence (whole protein): pLDDT 79.25, 28% of residues very-high.

**11 experimental structure(s)** (PDB): [4CAH](https://www.rcsb.org/structure/4CAH), [4CAI](https://www.rcsb.org/structure/4CAI), [4IHB](https://www.rcsb.org/structure/4IHB), [4IQH](https://www.rcsb.org/structure/4IQH), [7JOF](https://www.rcsb.org/structure/7JOF), [7K6B](https://www.rcsb.org/structure/7K6B) — incl. mutant structure 4IQH.

## What this gene does {#gene-function}

*Describes the biological roles of DYSF (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** DYSF's established molecular role includes calcium ion binding. p.Phe299fs falls in the c2 2 domain.


### Pathways affected {#pathways}

DYSF participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Smooth Muscle Contraction](https://reactome.org/content/detail/R-HSA-445355) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** calcium ion binding, phospholipid binding, calcium-dependent phospholipid binding.

**Biological process:** monocyte activation involved in immune response, macrophage activation involved in immune response, negative regulation of phagocytosis.

## Clinical significance {#significance}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-05-28.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2020–2025); classifications have been stable.

**ClinGen expert panel:** Pathogenic — Limb Girdle Muscular Dystrophy VCEP (autosomal recessive limb-girdle muscular dystrophy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PVS1`, `PM3_Supporting`, `PM2_Supporting`, `PP4_Strong`.
Inheritance: Autosomal recessive inheritance.

> **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.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50061 · approved 2025-05-28 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/f05d0b1b-36b6-454e-a404-5ce25ea211ad).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Pathogenic | no assertion criteria provided | clinical testing | 2020-12-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-03-28 |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Pathogenic | reviewed by expert panel | curation | 2025-05-28 |

## Associated conditions {#conditions}

[autosomal recessive limb-girdle muscular dystrophy](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy/), [autosomal recessive limb-girdle muscular dystrophy type 2B](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2b/), [neuromuscular disease caused by qualitative or quantitative defects of dysferlin](https://sugi.bio/atlas/disease/neuromuscular-disease-caused-by-qualitative-or-quantitative-defects-of-dysferlin/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy, Neuromuscular disease caused by qualitative or quantitative defects of dysferlin, Autosomal recessive limb-girdle muscular dystrophy type 2B, Dysferlinopathy, Qualitative or quantitative defects of dysferlin, Limb-girdle muscular dystrophy, type 2B, MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 3, MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2, Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B).

## Similar variants {#similar}

Related DYSF variant pages (same residue, condition, or type): [DYSF c.240-159_345+1237del](/variant/dysf-c-240-minus-159-345-plus-1237del), [DYSF c.345+1del](/variant/dysf-c-345-plus-1del), [DYSF c.3756+905_3897+151del](/variant/dysf-c-3756-plus-905-3897-plus-151del), [DYSF c.5885-51_6063+50del](/variant/dysf-c-5885-minus-51-6063-plus-50del), [DYSF c.92-1496_239+950del](/variant/dysf-c-92-minus-1496-239-plus-950del), [DYSF c.951+1del](/variant/dysf-c-951-plus-1del), [DYSF p.Ala927Leufs](/variant/dysf-p-ala927leufs), [DYSF p.Arg1759fs](/variant/dysf-p-arg1759fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 639814). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*