FLNC

Chr 7AD

filamin C

Also known as: ABP-280, ABP280A, ABPA, ABPL, ARVC15, CMH26, FLN2, MFM5

NCBI Gene: 2318 ENSG00000128591 UniProt: Q14315

This gene encodes one of three related filamin genes, specifically gamma filamin. These filamin proteins crosslink actin filaments into orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins for the actin cytoskeleton. Three functional domains exist in filamin: an N-terminal filamentous actin-binding domain, a C-terminal self-association domain, and a membrane glycoprotein-binding domain. Mutations in this gene are a cause of cardiopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2022]

Primary Disease Associations & Inheritance

Arrhythmogenic right ventricular dysplasia, familialMIM #617047

Cardiomyopathy, familial hypertrophic, 26MIM #617047

Cardiomyopathy, familial restrictive 5MIM #617047

Myopathy, distal, 4MIM #614065

Myopathy, myofibrillar, 5MIM #609524

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— FLNC

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

💊

Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Some data sources returned errors (1)

clinvarCount: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

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.

0.25LOEUF

pLI 1.000

Z-score 7.96

OE 0.17 (0.12–0.25)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.

2.79Z-score

OE missense 0.81 (0.77–0.85)

1369 obs / 1691.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.17 (0.12–0.25)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.77–0.85)

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.1.03

0≤1.21.6

LoF obs/exp: 18 / 106.7Missense obs/exp: 1369 / 1691.8Syn Z: -0.68

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

FLNC · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

FLNC-related myofibrillar myopathy

definitive

ADUndeterminedAltered Gene Product Structure

Cardiac

G2P ↗

missense variantinframe deletionstop gained NMD escaping

FLNC-related dilated cardiomyopathy

definitive

ADLoss Of FunctionDecreased Gene Product Level

Cardiac

G2P ↗

splice acceptor variantsplice donor variantframeshift variantstop gainedstop gained NMD triggeringframeshift variant NMD triggering

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

FILAMIN C; FLNC

MIM #102565 · *

Arrhythmogenic right ventricular dysplasia, familial

MIM #617047