cardiac valvular dysplasia, X-linked

Summary

cardiac valvular dysplasia, X-linked (MONDO:0010753) is a disease caused by FLNA (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: FLNA (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 103

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cardiac valvular dysplasia, X-linked
Mondo ID	MONDO:0010753
MeSH	C535576
OMIM	314400
Orphanet	1864, 555877
DOID	DOID:0111765
SNOMED CT	718128009
UMLS	C0262436
MedGen	78083
GARD	0001096
Is cancer (heuristic)	no

Also known as: cardiac valvular dysplasia, X-linked · congenital valvular dysplasia · CVD1 · myxomatous valvular dystrophy, X-linked · valvular heart disease, congenital · XMVD

Data availability: 103 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart valve disorder › tricuspid valve disorder › congenital tricuspid malformation › cardiac valvular dysplasia, X-linked

Related subtypes (9): tricuspid valve prolapse, Ebstein anomaly, tricuspid atresia, tricuspid valve agenesis, congenital tricuspid stenosis, straddling or overriding tricuspid valve, accessory tricuspid valve tissue, anomaly of the tricuspid valve chordae, parachute tricuspid valve

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

103 retrieved; paginated sample, class counts are floors:

31 conflicting classifications of pathogenicity, 31 uncertain significance, 15 benign/likely benign, 7 pathogenic, 6 pathogenic/likely pathogenic, 5 likely benign, 5 likely pathogenic, 2 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
141534	NM_000051.4(ATM):c.3894dup (p.Ala1299fs)	ATM	Pathogenic	criteria provided, multiple submitters, no conflicts
11776	NM_001110556.2(FLNA):c.1910C>A (p.Pro637Gln)	FLNA	Pathogenic	no assertion criteria provided
11777	NM_001110556.2(FLNA):c.862G>A (p.Gly288Arg)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11778	NM_001110556.2(FLNA):c.2132T>A (p.Val711Asp)	FLNA	Pathogenic	no assertion criteria provided
11779	NM_001110556.2(FLNA):c.2280+266_2827-25delinsTG	FLNA	Pathogenic	no assertion criteria provided
2035128	NM_001110556.2(FLNA):c.4598+1G>A	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209154	NM_001110556.2(FLNA):c.4726G>A (p.Gly1576Arg)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382382	NM_001110556.2(FLNA):c.6709_6710dup (p.Ala2238fs)	FLNA	Pathogenic	criteria provided, single submitter
3382665	NM_001110556.2(FLNA):c.5293C>T (p.Gln1765Ter)	FLNA	Pathogenic	criteria provided, single submitter
635974	NM_001110556.2(FLNA):c.1829-1G>C	FLNA	Pathogenic	no assertion criteria provided
635975	NM_001110556.2(FLNA):c.4660G>A (p.Gly1554Arg)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
871720	NM_001110556.2(FLNA):c.4750_4755+18del	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
931351	NM_001110556.2(FLNA):c.1924G>T (p.Glu642Ter)	FLNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2431207	NM_001110556.2(FLNA):c.7306G>A (p.Gly2436Arg)	FLNA	Likely pathogenic	criteria provided, single submitter
4292411	NM_001110556.2(FLNA):c.5332_5339del (p.Val1778fs)	FLNA	Likely pathogenic	criteria provided, single submitter
4294528	NM_001110556.2(FLNA):c.2193C>A (p.Tyr731Ter)	FLNA	Likely pathogenic	criteria provided, single submitter
4532195	NM_001110556.2(FLNA):c.2023-6_2026delinsACGCT	FLNA	Likely pathogenic	criteria provided, single submitter
930545	NM_001110556.2(FLNA):c.622+5G>C	FLNA	Likely pathogenic	criteria provided, single submitter
1011953	NM_001110556.2(FLNA):c.2392G>A (p.Glu798Lys)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030401	NM_001110556.2(FLNA):c.1349T>C (p.Met450Thr)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033845	NM_001110556.2(FLNA):c.3886C>T (p.Arg1296Cys)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1041672	NM_001110556.2(FLNA):c.1060C>T (p.His354Tyr)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1063162	NM_001110556.2(FLNA):c.2590G>T (p.Val864Phe)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
11770	NM_001110556.2(FLNA):c.1923C>T (p.Gly641=)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1500525	NM_001110556.2(FLNA):c.4625C>T (p.Thr1542Ile)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1524454	NM_001110556.2(FLNA):c.7834C>T (p.Arg2612Trp)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198133	NM_001110556.2(FLNA):c.901C>T (p.Arg301Trp)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1992401	NM_001110556.2(FLNA):c.3965C>T (p.Thr1322Met)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211017	NM_001110556.2(FLNA):c.4517C>T (p.Thr1506Ile)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211024	NM_001110556.2(FLNA):c.6719A>G (p.Lys2240Arg)	FLNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 30 · Orphanet: 19 · 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
FLNA	Definitive	X-linked	heterotopia, periventricular, X-linked dominant	30

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FLNA	Orphanet:1826	Frontometaphyseal dysplasia
FLNA	Orphanet:2301	Congenital short bowel syndrome
FLNA	Orphanet:2484	Melnick-Needles syndrome
FLNA	Orphanet:482606	X-linked keloid scarring-reduced joint mobility-increased optic cup-to-disc ratio syndrome
FLNA	Orphanet:555877	FLNA-related X-linked myxomatous valvular dysplasia
FLNA	Orphanet:75497	X-linked Ehlers-Danlos syndrome
FLNA	Orphanet:88630	Terminal osseous dysplasia-pigmentary defects syndrome
FLNA	Orphanet:90650	Otopalatodigital syndrome type 1
FLNA	Orphanet:90652	Otopalatodigital syndrome type 2
FLNA	Orphanet:98892	Periventricular nodular heterotopia
FLNA	Orphanet:99811	Neuronal intestinal pseudoobstruction
ATM	Orphanet:100	Ataxia-telangiectasia
ATM	Orphanet:1331	Familial prostate cancer
ATM	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
ATM	Orphanet:227535	Hereditary breast cancer
ATM	Orphanet:370109	Ataxia-telangiectasia variant
ATM	Orphanet:440437	Familial colorectal cancer Type X
ATM	Orphanet:52416	Mantle cell lymphoma
ATM	Orphanet:67038	B-cell chronic lymphocytic leukemia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	gencc,clinvar
ATM	HGNC:795	ENSG00000149311	Q13315	Serine-protein kinase ATM	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FLNA	Filamin-A	Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.
ATM	Serine-protein kinase ATM	Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	14.6×	0.071
Kinase	1	13.9×	0.071

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
ATM	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
popliteal artery	1
right coronary artery	1
tibial artery	1
calcaneal tendon	1
colonic epithelium	1
corpus callosum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FLNA	285	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
ATM	286	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATM	7,383
FLNA	5,321

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FLNA	P21333	26
ATM	Q13315	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 66. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sensing of DNA Double Strand Breaks	1	951.7×	0.012	ATM
OAS antiviral response	1	634.4×	0.012	FLNA
GP1b-IX-V activation signalling	1	475.8×	0.012	FLNA
TP53 Regulates Transcription of Caspase Activators and Caspases	1	475.8×	0.012	ATM
Pexophagy	1	475.8×	0.012	ATM
Defective homologous recombination repair (HRR) due to PALB2 loss of function	1	475.8×	0.012	ATM
Diseases of DNA Double-Strand Break Repair	1	407.9×	0.012	ATM
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	407.9×	0.012	ATM
Stabilization of p53	1	380.7×	0.012	ATM
p53-Dependent G1 DNA Damage Response	1	356.9×	0.012	ATM
p53-Dependent G1/S DNA damage checkpoint	1	356.9×	0.012	ATM
Cell-extracellular matrix interactions	1	335.9×	0.012	FLNA
G1/S DNA Damage Checkpoints	1	335.9×	0.012	ATM
Resolution of D-Loop Structures	1	317.2×	0.012	ATM
Diseases of DNA repair	1	285.5×	0.012	ATM
RHO GTPases activate PAKs	1	271.9×	0.012	FLNA
TP53 Regulates Transcription of Cell Death Genes	1	271.9×	0.012	ATM
TP53 Regulates Transcription of Genes Involved in Cytochrome C Release	1	271.9×	0.012	ATM
Regulation of TP53 Activity through Methylation	1	271.9×	0.012	ATM
Regulation of TP53 Expression and Degradation	1	259.6×	0.012	ATM
DNA Double Strand Break Response	1	237.9×	0.012	ATM
Impaired BRCA2 binding to PALB2	1	228.4×	0.012	ATM
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	211.5×	0.012	ATM
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	211.5×	0.012	ATM
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	211.5×	0.012	ATM
Cellular response to heat stress	1	196.9×	0.012	ATM
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	196.9×	0.012	ATM
Homologous DNA Pairing and Strand Exchange	1	190.3×	0.012	ATM
Homology Directed Repair	1	154.3×	0.013	ATM
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	154.3×	0.013	ATM

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of membrane repolarization during atrial cardiac muscle cell action potential	1	8426.0×	0.004	FLNA
regulation of membrane repolarization during cardiac muscle cell action potential	1	8426.0×	0.004	FLNA
establishment of RNA localization to telomere	1	4213.0×	0.004	ATM
establishment of protein-containing complex localization to telomere	1	4213.0×	0.004	ATM
positive regulation of telomerase catalytic core complex assembly	1	4213.0×	0.004	ATM
pre-B cell allelic exclusion	1	2808.7×	0.004	ATM
cellular response to nitrosative stress	1	2808.7×	0.004	ATM
tubulin deacetylation	1	2808.7×	0.004	FLNA
protein stabilization	2	66.9×	0.004	FLNA, ATM
formation of radial glial scaffolds	1	2106.5×	0.004	FLNA
adenylate cyclase-inhibiting dopamine receptor signaling pathway	1	1685.2×	0.004	FLNA
peptidyl-serine autophosphorylation	1	1685.2×	0.004	ATM
establishment of Sertoli cell barrier	1	1685.2×	0.004	FLNA
negative regulation of telomere capping	1	1685.2×	0.004	ATM
regulation of telomere maintenance via telomerase	1	1404.3×	0.004	ATM
protein localization to bicellular tight junction	1	1404.3×	0.004	FLNA
positive regulation of telomere maintenance via telomere lengthening	1	1404.3×	0.004	ATM
negative regulation of transcription by RNA polymerase I	1	1203.7×	0.005	FLNA
lipoprotein catabolic process	1	1203.7×	0.005	ATM
blood coagulation, intrinsic pathway	1	1053.2×	0.005	FLNA
V(D)J recombination	1	1053.2×	0.005	ATM
meiotic telomere clustering	1	936.2×	0.005	ATM
female meiotic nuclear division	1	842.6×	0.005	ATM
histone mRNA catabolic process	1	842.6×	0.005	ATM
cellular response to X-ray	1	842.6×	0.005	ATM
DNA double-strand break processing	1	766.0×	0.005	ATM
positive regulation of platelet activation	1	648.1×	0.006	FLNA
positive regulation of integrin-mediated signaling pathway	1	648.1×	0.006	FLNA
positive regulation of actin filament bundle assembly	1	601.9×	0.006	FLNA
actin crosslink formation	1	601.9×	0.006	FLNA

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ATM	AMIODARONE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATM	35	4
FLNA	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMIODARONE HYDROCHLORIDE	4	ATM
FURAZOLIDONE	4	ATM
ESTRADIOL ACETATE	4	ATM
NAFTIFINE HYDROCHLORIDE	4	ATM
METHYSERGIDE MALEATE	4	ATM
AMITRIPTYLINE HYDROCHLORIDE	4	ATM
XYLOMETAZOLINE HYDROCHLORIDE	4	ATM
FLUVOXAMINE MALEATE	4	ATM
ESTRADIOL VALERATE	4	ATM
PERMETHRIN	4	ATM
MITOTANE	4	ATM
TICLOPIDINE HYDROCHLORIDE	4	ATM
ENOXIMONE	4	ATM
METHYLENE BLUE ANHYDROUS	4	ATM
DITHIAZANINE IODIDE	4	ATM
ETHACRYNIC ACID	4	ATM
SECNIDAZOLE	4	ATM
MENADIONE	4	ATM
FENOFIBRATE	4	ATM
DIPYRIDAMOLE	4	ATM
DACTOLISIB	3	ATM
MOLIBRESIB	2	FLNA
STREPTONIGRIN	2	ATM
CALCIMYCIN	2	ATM
ENPIROLINE	2	ATM
OXACEPROL	2	ATM
TOLONIUM CHLORIDE	2	ATM
ESTRADIOL BENZOATE	2	ATM
BERZOSERTIB	2	ATM
LARTESERTIB	2	ATM

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ATM	240	Binding:233, Functional:5, ADMET:2
FLNA	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATM	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ATM	240

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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.

Compound	Max phase	Cohort target (bioactivity)
AMIODARONE HYDROCHLORIDE	4	ATM
FURAZOLIDONE	4	ATM
ESTRADIOL ACETATE	4	ATM
NAFTIFINE HYDROCHLORIDE	4	ATM
METHYSERGIDE MALEATE	4	ATM
AMITRIPTYLINE HYDROCHLORIDE	4	ATM
XYLOMETAZOLINE HYDROCHLORIDE	4	ATM
FLUVOXAMINE MALEATE	4	ATM
ESTRADIOL VALERATE	4	ATM
PERMETHRIN	4	ATM
MITOTANE	4	ATM
TICLOPIDINE HYDROCHLORIDE	4	ATM
ENOXIMONE	4	ATM
METHYLENE BLUE ANHYDROUS	4	ATM
DITHIAZANINE IODIDE	4	ATM
ETHACRYNIC ACID	4	ATM
SECNIDAZOLE	4	ATM
MENADIONE	4	ATM
FENOFIBRATE	4	ATM
DIPYRIDAMOLE	4	ATM
DACTOLISIB	3	ATM
MOLIBRESIB	2	FLNA
STREPTONIGRIN	2	ATM
CALCIMYCIN	2	ATM
ENPIROLINE	2	ATM
OXACEPROL	2	ATM
TOLONIUM CHLORIDE	2	ATM
ESTRADIOL BENZOATE	2	ATM
BERZOSERTIB	2	ATM
LARTESERTIB	2	ATM

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ATM
B	Phased (≥1) drug, not yet approved	1	FLNA
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.