Distal myopathy with posterior leg and anterior hand involvement

Summary

Distal myopathy with posterior leg and anterior hand involvement (MONDO:0013550) is a disease caused by FLNC (GenCC Strong), with 6 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FLNC (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 5,185
• Phenotypes (HPO): 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		16	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0008954	Intrinsic hand muscle atrophy	Very frequent (80-99%)
HP:0003738	Exercise-induced myalgia	Very frequent (80-99%)
HP:0002600	Hyporeflexia of lower limbs	Very frequent (80-99%)
HP:0002540	Inability to walk	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0031177	Finger flexor weakness	Frequent (30-79%)
HP:0009053	Distal lower limb muscle weakness	Frequent (30-79%)
HP:0009027	Foot dorsiflexor weakness	Frequent (30-79%)
HP:0006389	Limited knee flexion	Frequent (30-79%)
HP:0012515	Hip flexor weakness	Frequent (30-79%)
HP:0002141	Gait imbalance	Frequent (30-79%)
HP:0009046	Difficulty running	Frequent (30-79%)
HP:0008959	Distal upper limb muscle weakness	Occasional (5-29%)
HP:0030319	Weakness of facial musculature	Occasional (5-29%)
HP:0001626	Abnormality of the cardiovascular system	Occasional (5-29%)
HP:0030200	Fatiguable weakness of proximal limb muscles	Occasional (5-29%)
HP:0006135	Decreased finger mobility	Occasional (5-29%)
HP:0008994	Proximal muscle weakness in lower limbs	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0002015	Dysphagia	Excluded (0%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Excluded (0%)
HP:0003474	Somatic sensory dysfunction	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	distal myopathy with posterior leg and anterior hand involvement
Mondo ID	MONDO:0013550
OMIM	614065
Orphanet	63273
DOID	DOID:0111190
SNOMED CT	733489002
UMLS	C3279722
MedGen	481352
GARD	0016666
Is cancer (heuristic)	no

Also known as: distal ABD-filaminopathy · MPD4 · myopathy, distal, 4 · myopathy, distal, type 4

Data availability: 5,185 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant distal myopathy › distal myopathy with posterior leg and anterior hand involvement

Related subtypes (14): tibial muscular dystrophy, myopathy, myofibrillar, 9, with early respiratory failure, distal myopathy, Welander type, myofibrillar myopathy 2, myofibrillar myopathy 3, myofibrillar myopathy 4, Finnish upper limb-onset distal myopathy, distal myopathy, Tateyama type, adult-onset distal myopathy due to VCP mutation, KLHL9-related early-onset distal myopathy, distal myopathy with vocal cord weakness, TARDBP-related predominantly upper-limb distal myopathy, asymetric thumb-handgrip weakness-distal myopathy, calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

267 likely benign, 204 uncertain significance, 47 conflicting classifications of pathogenicity, 39 pathogenic, 24 benign, 10 benign/likely benign, 7 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067540	NM_001458.5(FLNC):c.5199+1G>T	FLNC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068545	NM_001458.5(FLNC):c.6955del (p.Ala2319fs)	FLNC	Pathogenic	criteria provided, single submitter
1068586	NM_001458.5(FLNC):c.4432C>T (p.Gln1478Ter)	FLNC	Pathogenic	criteria provided, multiple submitters, no conflicts
1068631	NM_001458.5(FLNC):c.1205del (p.Thr402fs)	FLNC	Pathogenic	criteria provided, single submitter
1068840	NM_001458.5(FLNC):c.1991_1994del (p.Asp664fs)	FLNC	Pathogenic	criteria provided, single submitter
1068841	NM_001458.5(FLNC):c.3702del (p.Val1235fs)	FLNC	Pathogenic	criteria provided, single submitter
1069362	NM_001458.5(FLNC):c.1914C>G (p.Tyr638Ter)	FLNC	Pathogenic	criteria provided, multiple submitters, no conflicts
1069877	NM_001458.5(FLNC):c.2604del (p.Ser868fs)	FLNC	Pathogenic	criteria provided, single submitter
1070209	NM_001458.5(FLNC):c.4718T>A (p.Leu1573Ter)	FLNC	Pathogenic	criteria provided, multiple submitters, no conflicts
1070523	NM_001458.5(FLNC):c.5520T>A (p.Tyr1840Ter)	FLNC	Pathogenic	criteria provided, multiple submitters, no conflicts
1070569	NM_001458.5(FLNC):c.6802G>T (p.Glu2268Ter)	FLNC	Pathogenic	criteria provided, single submitter
1070575	NM_001458.5(FLNC):c.4755del (p.Lys1586fs)	FLNC	Pathogenic	criteria provided, single submitter
1071490	NM_001458.5(FLNC):c.1670del (p.Pro557fs)	FLNC	Pathogenic	criteria provided, single submitter
1071491	NM_001458.5(FLNC):c.5733dup (p.Gly1912fs)	FLNC	Pathogenic	criteria provided, single submitter
1071678	NM_001458.5(FLNC):c.5569_5578del (p.Ile1857fs)	FLNC	Pathogenic	criteria provided, single submitter
1071863	NC_000007.13:g.(?128470682)(128498587_?)del	FLNC	Pathogenic	criteria provided, single submitter
1071864	NC_000007.13:g.(?128469483)(128500328_?)del	FLNC	Pathogenic	criteria provided, single submitter
1071931	NM_001458.5(FLNC):c.261del (p.Pro88fs)	FLNC	Pathogenic	criteria provided, single submitter
1072180	NM_001458.5(FLNC):c.2499C>A (p.Tyr833Ter)	FLNC	Pathogenic	criteria provided, multiple submitters, no conflicts
1072269	NM_001458.5(FLNC):c.3070C>T (p.Gln1024Ter)	FLNC	Pathogenic	criteria provided, multiple submitters, no conflicts
1072270	NM_001458.5(FLNC):c.6240_6259del (p.Pro2081fs)	FLNC	Pathogenic	criteria provided, multiple submitters, no conflicts
1072629	NM_001458.5(FLNC):c.181C>T (p.Gln61Ter)	FLNC	Pathogenic	criteria provided, single submitter
1073366	NM_001458.5(FLNC):c.4946del (p.Gly1649fs)	FLNC	Pathogenic	criteria provided, multiple submitters, no conflicts
1073410	NM_001458.5(FLNC):c.156dup (p.Val53fs)	FLNC	Pathogenic	criteria provided, single submitter
1074200	NM_001458.5(FLNC):c.5557del (p.Tyr1853fs)	FLNC	Pathogenic	criteria provided, single submitter
1074377	NM_001458.5(FLNC):c.563del (p.Gly188fs)	FLNC	Pathogenic	criteria provided, single submitter
1074392	NM_001458.5(FLNC):c.2548C>T (p.Gln850Ter)	FLNC	Pathogenic	criteria provided, single submitter
1074694	NM_001458.5(FLNC):c.146_147insT (p.Leu50fs)	FLNC	Pathogenic	criteria provided, single submitter
1074904	NM_001458.5(FLNC):c.1893G>A (p.Trp631Ter)	FLNC	Pathogenic	criteria provided, single submitter
1075295	NM_001458.5(FLNC):c.4275dup (p.Arg1426fs)	FLNC	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FLNC	Definitive	Autosomal dominant	myofibrillar myopathy 5	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLNC	Orphanet:171445	Muscle filaminopathy
FLNC	Orphanet:63273	FLNC-related handgrip and calf weakness-distal myopathy
FLNC	Orphanet:75249	Familial isolated restrictive cardiomyopathy
TNPO3	Orphanet:186	Primary biliary cholangitis
TNPO3	Orphanet:55595	TNP03-related limb-girdle muscular dystrophy D2
ADCY5	Orphanet:1429	Benign hereditary chorea
ADCY5	Orphanet:324588	Familial dyskinesia and facial myokymia

Cohort genes → proteins

6 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FLNC	HGNC:3756	ENSG00000128591	Q14315	Filamin-C	gencc,clinvar
ATP6V1F	HGNC:16832	ENSG00000128524	Q16864	V-type proton ATPase subunit F	clinvar
TNPO3	HGNC:17103	ENSG00000064419	Q9Y5L0	Transportin-3	clinvar
FRMD1	HGNC:21240	ENSG00000153303	Q8N878	FERM domain-containing protein 1	clinvar
ADCY5	HGNC:236	ENSG00000173175	O95622	Adenylate cyclase type 5	clinvar
FLNC-AS1	HGNC:53474	ENSG00000242902		FLNC antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FLNC	Filamin-C	Muscle-specific filamin, which plays a central role in sarcomere assembly and organization.
ATP6V1F	V-type proton ATPase subunit F	Subunit of the V1 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
TNPO3	Transportin-3	Importin, which transports target proteins into the nucleus.
ADCY5	Adenylate cyclase type 5	Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	4.9×	0.458
Enzyme (other)	1	2.0×	0.458
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLNC	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
ATP6V1F	Other/Unknown	no		ATPase_V1-cplx_fsu_euk, ATPase_V1-cplx_f_g_su, ATPase_V1_fsu_sf
TNPO3	Other/Unknown	no		ARM-like, Exportin-1/Importin-b-like, ARM-type_fold
FRMD1	Other/Unknown	no		FERM_domain, FERM/acyl-CoA-bd_prot_sf, FERM_N
ADCY5	Enzyme (other)	yes	4.6.1.1	A/G_cyclase, Adcy_conserved_dom, A/G_cyclase_CS
FLNC-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	2
apex of heart	2
gastrocnemius	1
tibialis anterior	1
left testis	1
prefrontal cortex	1
right testis	1
medial globus pallidus	1
secondary oocyte	1
tendon of biceps brachii	1
body of stomach	1
mucosa of transverse colon	1
sural nerve	1
lower esophagus	1
lower esophagus muscularis layer	1
muscle of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLNC	255	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, tibialis anterior
ATP6V1F	294	ubiquitous	marker	prefrontal cortex, left testis, right testis
TNPO3	299	ubiquitous	marker	secondary oocyte, tendon of biceps brachii, medial globus pallidus
FRMD1	115	tissue_specific	marker	mucosa of transverse colon, sural nerve, body of stomach
ADCY5	193	broad	marker	apex of heart, lower esophagus muscularis layer, lower esophagus
FLNC-AS1	114		yes	hindlimb stylopod muscle, apex of heart, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FLNC	3,174
TNPO3	2,970
ATP6V1F	2,214
ADCY5	1,992
FRMD1	819
FLNC-AS1	0

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLNC	Q14315	14
ATP6V1F	Q16864	8
TNPO3	Q9Y5L0	6
ADCY5	O95622	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FRMD1	Q8N878	66.72

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 56. Enrichment computed across 6 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Adenylate cyclase activating pathway	1	380.7×	0.021	ADCY5
Adenylate cyclase inhibitory pathway	1	253.8×	0.021	ADCY5
PKA activation in glucagon signalling	1	223.9×	0.021	ADCY5
Cell-extracellular matrix interactions	1	223.9×	0.021	FLNC
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	223.9×	0.021	ATP6V1F
PKA activation	1	211.5×	0.021	ADCY5
Activation of GABAB receptors	1	200.3×	0.021	ADCY5
PKA-mediated phosphorylation of CREB	1	190.3×	0.021	ADCY5
GABA B receptor activation	1	181.3×	0.021	ADCY5
Adrenaline,noradrenaline inhibits insulin secretion	1	131.3×	0.021	ADCY5
Anti-inflammatory response favouring Leishmania parasite infection	1	131.3×	0.021	ADCY5
Leishmania parasite growth and survival	1	131.3×	0.021	ADCY5
Calmodulin induced events	1	126.9×	0.021	ADCY5
CaM pathway	1	126.9×	0.021	ADCY5
Insulin receptor recycling	1	126.9×	0.021	ATP6V1F
Ca-dependent events	1	122.8×	0.021	ADCY5
Aquaporin-mediated transport	1	122.8×	0.021	ADCY5
Transferrin endocytosis and recycling	1	122.8×	0.021	ATP6V1F
Glucagon signaling in metabolic regulation	1	115.3×	0.021	ADCY5
ROS and RNS production in phagocytes	1	112.0×	0.021	ATP6V1F
G-protein mediated events	1	108.8×	0.021	ADCY5
DAG and IP3 signaling	1	105.7×	0.021	ADCY5
GABA receptor activation	1	105.7×	0.021	ADCY5
Response of endothelial cells to shear stress	1	100.2×	0.021	ADCY5
FCGR3A-mediated IL10 synthesis	1	97.6×	0.021	ADCY5
Opioid Signalling	1	88.5×	0.021	ADCY5
PLC beta mediated events	1	88.5×	0.021	ADCY5
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	1	88.5×	0.021	ADCY5
Vasopressin regulates renal water homeostasis via Aquaporins	1	88.5×	0.021	ADCY5
Cellular responses to mechanical stimuli	1	86.5×	0.021	ADCY5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
adenylate cyclase-inhibiting dopamine receptor signaling pathway	1	674.1×	0.012	ADCY5
G protein-coupled adenosine receptor signaling pathway	1	481.5×	0.012	ADCY5
Golgi lumen acidification	1	337.0×	0.012	ATP6V1F
adenylate cyclase-activating dopamine receptor signaling pathway	1	306.4×	0.012	ADCY5
cAMP biosynthetic process	1	280.9×	0.012	ADCY5
endosomal lumen acidification	1	240.7×	0.012	ATP6V1F
intracellular pH reduction	1	240.7×	0.012	ATP6V1F
cellular response to forskolin	1	224.7×	0.012	ADCY5
positive regulation of hippo signaling	1	210.7×	0.012	FRMD1
regulation of insulin secretion involved in cellular response to glucose stimulus	1	187.2×	0.012	ADCY5
synaptic vesicle lumen acidification	1	187.2×	0.012	ATP6V1F
cellular response to glucagon stimulus	1	168.5×	0.012	ADCY5
vacuolar acidification	1	146.5×	0.012	ATP6V1F
vascular endothelial cell response to laminar fluid shear stress	1	146.5×	0.012	ADCY5
lysosomal lumen acidification	1	134.8×	0.012	ATP6V1F
renal water homeostasis	1	102.1×	0.015	ADCY5
sarcomere organization	1	76.6×	0.018	FLNC
neuromuscular process controlling balance	1	66.1×	0.020	ADCY5
proton transmembrane transport	1	62.4×	0.020	ATP6V1F
locomotory behavior	1	35.9×	0.033	ADCY5
protein import into nucleus	1	28.8×	0.039	TNPO3
positive regulation of cytosolic calcium ion concentration	1	23.4×	0.045	ADCY5
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	22.6×	0.045	ADCY5
intracellular signal transduction	1	7.6×	0.124	ADCY5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 2 of 6 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FLNC	0	0
ATP6V1F	0	0
TNPO3	0	0
FRMD1	0	0
ADCY5	0	0
FLNC-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ADCY5	43	Binding:33, Functional:9, ADMET:1
TNPO3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADCY5	4.6.1.1	adenylate cyclase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	FLNC, ADCY5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	ATP6V1F, TNPO3, FRMD1, FLNC-AS1

Undrugged target profiles

6 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FLNC	0	—
ATP6V1F	0	—
TNPO3	1	—
FRMD1	0	—
ADCY5	43	—
FLNC-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.