# NM_001458.5(FLNC):c.2787del (p.Val930fs)

https://sugi.bio/variant/flnc-p-val930fs

## Summary

**FLNC p.Val930fs (c.2787del)** is classified **Pathogenic** in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-15). No gnomAD frequency available for this variant; Associated with myofibrillar myopathy 5.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2536634035 · 1 submitter · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the FLNC gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to myofibrillar myopathy 5.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | FLNC is a diagnostic-grade gene on 10 Genomics England panels |

**Commonly reported features of Muscle filaminopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- EMG: myopathic abnormalities — Very frequent (99-80%)
- Mildly elevated creatine kinase — Very frequent (99-80%)
- Proximal muscle weakness in lower limbs — Very frequent (99-80%)
- Gait disturbance — Frequent (79-30%)
- Respiratory insufficiency — Frequent (79-30%)
- Back pain — Frequent (79-30%)
- Difficulty climbing stairs — Frequent (79-30%)
- Muscle fiber splitting — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017062/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FLNC](https://sugi.bio/atlas/gene/FLNC/) |
| Protein change (HGVS p.) | p.Val930fs |
| Coding change (HGVS c.) | c.2787del |
| MANE Select transcript | [NM_001458](https://www.ncbi.nlm.nih.gov/nuccore/NM_001458) |
| dbSNP | [rs2536634035](https://www.ncbi.nlm.nih.gov/snp/rs2536634035/) |
| Variant type | Deletion |
| Location | chr7:128843553-128843553 (GRCh38) |
| ClinVar | [VCV2945328](https://www.ncbi.nlm.nih.gov/clinvar/variation/2945328/) |

**All HGVS expressions:** `LRG_870:g.18125del`, `LRG_870t1:c.2787del`, `NC_000007.13:g.128483607del`, `NC_000007.14:g.128843553del`, `NG_011807.1:g.18125del`, `NM_001127487.2:c.2787del`, `NM_001458.5:c.2787del`

## 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 7.666, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.424, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 18 of 48**, 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**FLNC** population constraint: LOEUF 0.424, pLI 1, missense-Z 5.9661; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **myofibrillar myopathy** — Definitive (AD)
- **dilated cardiomyopathy** — Definitive (AD)

## Protein context {#protein}

Residue **930** lies in a UniProt-annotated variant site (in mfm5; uncertain significance).

**14 experimental structure(s)** (PDB): [1V05](https://www.rcsb.org/structure/1V05), [2D7M](https://www.rcsb.org/structure/2D7M), [2D7N](https://www.rcsb.org/structure/2D7N), [2D7O](https://www.rcsb.org/structure/2D7O), [2D7P](https://www.rcsb.org/structure/2D7P), [2D7Q](https://www.rcsb.org/structure/2D7Q).

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

*Describes the biological roles of FLNC (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:** FLNC's established molecular role includes cytoskeletal protein binding.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cell-extracellular matrix interactions](https://reactome.org/content/detail/R-HSA-446353) | curated |

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

**Molecular function:** cytoskeletal protein binding, ankyrin binding, identical protein binding.

**Biological process:** sarcomere organization.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-15.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-03-15 |

## Associated conditions {#conditions}

[myofibrillar myopathy 5](https://sugi.bio/atlas/disease/myofibrillar-myopathy-5/), [distal myopathy with posterior leg and anterior hand involvement](https://sugi.bio/atlas/disease/distal-myopathy-with-posterior-leg-and-anterior-hand-involvement/), [hypertrophic cardiomyopathy 26](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy-26/).

**Reported phenotype names (ClinVar):** Myofibrillar myopathy 5, Distal myopathy with posterior leg and anterior hand involvement, Hypertrophic cardiomyopathy 26, not provided, Filaminopathy (type), FILAMINOPATHY, AUTOSOMAL DOMINANT, none provided, Cardiomyopathy, familial hypertrophic, 26, WILLIAMS DISTAL MYOPATHY.

## Similar variants {#similar}

Related FLNC variant pages (same residue, condition, or type): [FLNC p.Val930_Thr933del](/variant/flnc-p-val930-thr933del), [FLNC p.Val930=](/variant/flnc-p-val930), [FLNC c.2390-10_2406del](/variant/flnc-c-2390-minus-10-2406del), [FLNC c.2929+2_2929+7del](/variant/flnc-c-2929-plus-2-2929-plus-7del), [FLNC p.Ala1902fs](/variant/flnc-p-ala1902fs), [FLNC p.Ala260fs](/variant/flnc-p-ala260fs), [FLNC p.Ala656fs](/variant/flnc-p-ala656fs), [FLNC p.Arg1352fs](/variant/flnc-p-arg1352fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2945328). 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.*