# NM_001130987.2(DYSF):c.1350del (p.Phe451fs)

https://sugi.bio/variant/dysf-p-phe451fs

## Summary

**DYSF p.Phe451fs (c.1350del)** is classified **Pathogenic** in DYSF (ClinVar, Expert panel, 4 submitters; last evaluated 2025-09-17). Very rare (popmax 8.47e-05%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy.

**At a glance:** Pathogenic · review: Expert panel · rsID rs766936914 · 4 submitters · 4 linked conditions · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the DYSF gene that is considered disease-causing, submitted by 4 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.Phe451fs |
| Coding change (HGVS c.) | c.1350del |
| MANE Select transcript | [NM_001130987](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130987) |
| dbSNP | [rs766936914](https://www.ncbi.nlm.nih.gov/snp/rs766936914/) |
| Variant type | Deletion |
| Location | chr2:71528368-71528368 (GRCh38) |
| ClinVar | [VCV551669](https://www.ncbi.nlm.nih.gov/clinvar/variation/551669/) |

**All HGVS expressions:** `LRG_845:g.79749del`, `LRG_845t1:c.1254del`, `LRG_845t2:c.1350del`, `NC_000002.11:g.71755501del`, `NC_000002.12:g.71528371del`, `NG_008694.1:g.79749del`, `NM_001130455.2:c.1257del`, `NM_001130976.2:c.1254del`, `NM_001130977.2:c.1254del`, `NM_001130978.2:c.1254del`, `NM_001130979.2:c.1347del`, `NM_001130980.2:c.1347del`, `NM_001130981.2:c.1347del`, `NM_001130982.2:c.1350del`, `NM_001130983.2:c.1257del`, `NM_001130984.2:c.1257del`, `NM_001130985.2:c.1350del`, `NM_001130986.2:c.1257del`, `NM_001130987.2:c.1350del`, `NM_003494.4:c.1254del`

## 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 10.8, GERP 2.14, 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 14 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 **8.47e-05%** (nfe) · 1/1,180,008 in the highest group · 1/1,461,836 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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 **451** lies in a β-strand; the c2 3 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.Phe451fs falls in the c2 3 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 2025-09-17.

**Submitter consensus:** unanimous (4/4 Pathogenic).

**Submission history:** 4 submissions (2017–2025); 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.1254del p.(Phe419LeufsTer41) variant in DYSF, which is also known as NM_001130987.2: c.1350del p.(Phe451LeufsTer41), is a frameshift variant expected to introduce a premature stop codon in exon 15/55, leading to nonsense mediated decay in a gene in which loss of function is a known mechanism of disease (PVS1). In the literature, this variant has also been described as p.(Pro418ProfsTer123). This variant has been reported in at least three patients with features consistent with LGMD (PMID: 27647186, 26404900, 26404900), including in a homozygous state without reported familial consanguinity (0.5 pts, PMID: 17994539; PM3_Supporting). This homozygous individual had both progressive limb girdle muscle weakness and absent dysferlin expression in skeletal muscle via both immunohistochemistry and Western blot (PMID: 17994539; PP4_Strong). The highest population allele frequency for this variant is 8.475e-7 in gnomAD v4.1.0 (1/1180008 European (non-Finnish) alleles), which is less than the threshold of 0.0001 for PM2_Supporting, meeting 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 2.0.0; 09/17/2025): PVS1, PM3_Supporting, PP4_Strong, PM2_Supporting.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50061 · approved 2025-09-17 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/4c9547ca-5c55-4e70-9c57-f110c35e4994).*
*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 |
| --- | --- | --- | --- | --- |
| Counsyl | Pathogenic | no assertion criteria provided | clinical testing | 2017-05-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-03-14 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-01-10 |
| ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen | Pathogenic | reviewed by expert panel | curation | 2025-09-17 |

## 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/), [Miyoshi muscular dystrophy 1](https://sugi.bio/atlas/disease/miyoshi-muscular-dystrophy-1/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy, Autosomal recessive limb-girdle muscular dystrophy type 2B, Neuromuscular disease caused by qualitative or quantitative defects of dysferlin, Miyoshi muscular dystrophy 1, Qualitative or quantitative defects of dysferlin, Dysferlinopathy, Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B), MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2, MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 3, Limb-girdle muscular dystrophy, type 2B.

## 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 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 551669). 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.*