# NM_001458.5(FLNC):c.1545del (p.Pro516fs)

https://sugi.bio/variant/flnc-p-pro516fs

## Summary

**FLNC p.Pro516fs (c.1545del)** is classified **Pathogenic** in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-18). Associated with hypertrophic cardiomyopathy 26.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 3 linked conditions

## 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 hypertrophic cardiomyopathy 26.

*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.*

|  |  |
| --- | --- |
| Diagnostic panels | FLNC is a diagnostic-grade gene on 10 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025029/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.Pro516fs |
| Coding change (HGVS c.) | c.1545del |
| MANE Select transcript | [NM_001458](https://www.ncbi.nlm.nih.gov/nuccore/NM_001458) |
| Variant type | Deletion |
| Location | chr7:128840153-128840153 (GRCh38) |
| ClinVar | [VCV4812550](https://www.ncbi.nlm.nih.gov/clinvar/variation/4812550/) |

**All HGVS expressions:** `LRG_870:g.14728del`, `LRG_870t1:c.1545del`, `NC_000007.13:g.128480210del`, `NC_000007.14:g.128840156del`, `NG_011807.1:g.14728del`, `NM_001127487.2:c.1545del`, `NM_001458.5:c.1545del`

## 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 11.2, 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 9 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.

*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}


**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 2025-11-18.

**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 | 2025-11-18 |

## Associated conditions {#conditions}

[hypertrophic cardiomyopathy 26](https://sugi.bio/atlas/disease/hypertrophic-cardiomyopathy-26/), [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/).

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

## Similar variants {#similar}

Related FLNC variant pages (same residue, condition, or type): [FLNC p.Pro516Ser](/variant/flnc-p-pro516ser), [FLNC p.Pro516Thr](/variant/flnc-p-pro516thr), [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 4812550). 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.*