Hypertrophic cardiomyopathy 9

Summary

Hypertrophic cardiomyopathy 9 (MONDO:0013412) is a disease with 6 cohort genes.

At a glance

• Cohort genes: 6
• ClinVar variants: 1,771

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertrophic cardiomyopathy 9
Mondo ID	MONDO:0013412
MeSH	C566044
OMIM	613765
DOID	DOID:0110315
UMLS	C1861065
MedGen	348780
GARD	0024921
Is cancer (heuristic)	no

Also known as: cardiomyopathy, familial hypertrophic, 9 · cardiomyopathy, familial hypertrophic, type 9 · CMH9 · hypertrophic cardiomyopathy caused by mutation in TTN · hypertrophic cardiomyopathy type 9 · TTN hypertrophic cardiomyopathy

Data availability: 1,771 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › hypertrophic cardiomyopathy › familial hypertrophic cardiomyopathy › hypertrophic cardiomyopathy 9

Related subtypes (39): hypertrophic cardiomyopathy 2, hypertrophic cardiomyopathy 3, hypertrophic cardiomyopathy 4, Beckwith-Wiedemann syndrome, myotonic dystrophy type 1, hypertrophic cardiomyopathy 1, very long chain acyl-CoA dehydrogenase deficiency, multiple acyl-CoA dehydrogenase deficiency, 46,XY complete gonadal dysgenesis, hypertrophic cardiomyopathy 6, dilated cardiomyopathy 1C, hypertrophic cardiomyopathy 25, hypertrophic cardiomyopathy 8, hypertrophic cardiomyopathy 10, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, cardiomyopathy-hypotonia-lactic acidosis syndrome, hypertrophic cardiomyopathy 11, hypertrophic cardiomyopathy 12, hypertrophic cardiomyopathy 13, hypertrophic cardiomyopathy 14, hypertrophic cardiomyopathy 15, hypertrophic cardiomyopathy 7, hypertrophic cardiomyopathy 16, hypertrophic cardiomyopathy 17, hypertrophic cardiomyopathy 18, hypertrophic cardiomyopathy 19, hypertrophic cardiomyopathy 20, hypertrophic cardiomyopathy 21, dilated cardiomyopathy 1KK, hypertrophic cardiomyopathy 26, Noonan syndrome and Noonan-related syndrome, long chain acyl-CoA dehydrogenase deficiency, cardiomyopathy, familial hypertrophic, 28, cardiomyopathy, familial hypertrophic 27, cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction, cardiomyopathy, familial restrictive, 5, cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, cardiomyopathy, familial hypertrophic, 30, atrial, cardiomyopathy, familial hypertrophic, 31

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:

338 uncertain significance, 161 conflicting classifications of pathogenicity, 33 likely benign, 30 pathogenic/likely pathogenic, 16 benign/likely benign, 15 likely pathogenic, 3 pathogenic, 2 not provided, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
202501	NM_001267550.2(TTN):c.4724_4728del (p.Met1575fs)	LOC101927055	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067013	NM_001267550.2(TTN):c.69421_69422insAAAAG (p.Gly23141fs)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12649	NM_001267550.2(TTN):c.2219G>T (p.Arg740Leu)	TTN	Pathogenic	no assertion criteria provided
12652	NM_001267550.2(TTN):c.107780_107790delinsTGAAAGAAAAA (p.Glu35927_Trp35930delinsValLysGluLys)	TTN	Pathogenic	criteria provided, multiple submitters, no conflicts
132133	NM_001267550.2(TTN):c.95134T>C (p.Cys31712Arg)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
132137	NM_001267550.2(TTN):c.95195C>T (p.Pro31732Leu)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329193	NM_001267550.2(TTN):c.73939C>T (p.Arg24647Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1508786	NM_001267550.2(TTN):c.80380C>T (p.Gln26794Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165720	NM_001267550.2(TTN):c.94180delinsTCTAGCAG (p.Pro31394fs)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
179411	NM_001267550.2(TTN):c.49648+2del	TTN	Pathogenic	criteria provided, multiple submitters, no conflicts
179759	NM_001267550.2(TTN):c.81321C>G (p.Tyr27107Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
195920	NM_001267550.2(TTN):c.60681dup (p.Lys20228Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202397	NM_001267550.2(TTN):c.61555C>T (p.Arg20519Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202399	NM_001267550.2(TTN):c.64999C>T (p.Arg21667Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202404	NM_001267550.2(TTN):c.73846C>T (p.Arg24616Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202416	NM_001267550.2(TTN):c.82639G>T (p.Glu27547Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202467	NM_001267550.2(TTN):c.75138_75141del (p.Lys25046fs)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202479	NM_001267550.2(TTN):c.83064_83073del (p.Ala27689fs)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202496	NM_001267550.2(TTN):c.97129_97130dup (p.Leu32379fs)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202521	NM_001267550.2(TTN):c.75328C>T (p.Arg25110Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
223295	NM_001267550.2(TTN):c.85090C>T (p.Arg28364Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
223314	NM_001267550.2(TTN):c.63601C>T (p.Arg21201Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
223315	NM_001267550.2(TTN):c.64453C>T (p.Arg21485Ter)	TTN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068361	NM_001267550.2(TTN):c.96669G>A (p.Trp32223Ter)	TTN-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180573	NM_001267550.2(TTN):c.67495C>T (p.Arg22499Ter)	TTN-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
196723	NM_001267550.2(TTN):c.107377+1G>A	TTN-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202400	NM_001267550.2(TTN):c.69250C>T (p.Arg23084Ter)	TTN-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202405	NM_001267550.2(TTN):c.74338C>T (p.Arg24780Ter)	TTN-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202409	NM_001267550.2(TTN):c.78178G>T (p.Glu26060Ter)	TTN-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202429	NM_001267550.2(TTN):c.101227C>T (p.Arg33743Ter)	TTN-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · 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
TTN	Definitive	Autosomal dominant	dilated cardiomyopathy 1G	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy
CORIN	Orphanet:275555	Preeclampsia
LRP4	Orphanet:3152	Sclerosteosis
LRP4	Orphanet:3258	Cenani-Lenz syndrome
LRP4	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
PMS2	Orphanet:144	Lynch syndrome
PMS2	Orphanet:252202	Constitutional mismatch repair deficiency syndrome

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
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	gencc,clinvar
CORIN	HGNC:19012	ENSG00000145244	Q9Y5Q5	Atrial natriuretic peptide-converting enzyme	clinvar
TTN-AS1	HGNC:44124	ENSG00000237298		TTN antisense RNA 1	clinvar
LRP4	HGNC:6696	ENSG00000134569	O75096	Low-density lipoprotein receptor-related protein 4	clinvar
MYOM1	HGNC:7613	ENSG00000101605	P52179	Myomesin-1	clinvar
PMS2	HGNC:9122	ENSG00000122512	P54278	Mismatch repair endonuclease PMS2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
CORIN	Atrial natriuretic peptide-converting enzyme	Serine-type endopeptidase involved in atrial natriuretic peptide (NPPA) and brain natriuretic peptide (NPPB) processing.
LRP4	Low-density lipoprotein receptor-related protein 4	Mediates SOST-dependent inhibition of bone formation.
MYOM1	Myomesin-1	Major component of the vertebrate myofibrillar M band.
PMS2	Mismatch repair endonuclease PMS2	Component of the post-replicative DNA mismatch repair system (MMR).

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.5

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
Protease	1	6.1×	0.264
Antibody/Immunoglobulin	1	4.9×	0.264
Kinase	1	4.6×	0.264
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
CORIN	Protease	yes		SRCR, Trypsin_dom, LDrepeatLR_classA_rpt
TTN-AS1	Other/Unknown	no
LRP4	Other/Unknown	no		LDLR_classB_rpt, EGF, EGF-like_Ca-bd_dom
MYOM1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
PMS2	Other/Unknown	no		MutL/Mlh/PMS, DNA_mismatch_S5_2-like, Ribsml_uS5_D2-typ_fold_subgr

Expression context

Cohort genes with no expression data: 0.

6 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
gluteal muscle	2
hindlimb stylopod muscle	2
biceps brachii	1
skeletal muscle tissue of biceps brachii	1
cardiac muscle of right atrium	1
heart right ventricle	1
myocardium	1
gastrocnemius	1
right atrium auricular region	1
dorsal motor nucleus of vagus nerve	1
medial globus pallidus	1
ventricular zone	1
skeletal muscle tissue of rectus abdominis	1
male germ line stem cell (sensu Vertebrata) in testis	1
prefrontal cortex	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
CORIN	176	tissue_specific	marker	cardiac muscle of right atrium, heart right ventricle, myocardium
TTN-AS1	174	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, right atrium auricular region
LRP4	242	ubiquitous	marker	ventricular zone, dorsal motor nucleus of vagus nerve, medial globus pallidus
MYOM1	215	broad	marker	hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis, gluteal muscle
PMS2	143	ubiquitous	marker	thymus, prefrontal cortex, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TTN	4,237
PMS2	2,658
CORIN	1,291
LRP4	1,250
MYOM1	1,082
TTN-AS1	0

Intra-cohort edges

A	B	Sources
MYOM1	TTN	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
MYOM1	P52179	9
PMS2	P54278	9
LRP4	O75096	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CORIN	Q9Y5Q5	70.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective Mismatch Repair Associated With MLH1	1	1427.5×	0.004	PMS2
Defective Mismatch Repair Associated With PMS2	1	1427.5×	0.004	PMS2
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	1	203.9×	0.012	PMS2
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	1	203.9×	0.012	PMS2
Physiological factors	1	167.9×	0.012	CORIN
Striated Muscle Contraction	1	77.2×	0.021	TTN
TP53 Regulates Transcription of DNA Repair Genes	1	45.3×	0.031	PMS2
ECM proteoglycans	1	37.6×	0.033	LRP4
Platelet degranulation	1	22.0×	0.050	TTN
Extracellular matrix organization	1	15.8×	0.062	LRP4

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
obsolete protein kinase A signaling	2	561.7×	3e-04	TTN, MYOM1
sarcomere organization	2	153.2×	0.002	TTN, MYOM1
positive regulation of protein secretion	2	137.6×	0.002	TTN, MYOM1
positive regulation of presynaptic membrane organization	1	3370.4×	0.004	LRP4
regulation of systemic arterial blood pressure by atrial natriuretic peptide	1	1123.5×	0.006	CORIN
skeletal muscle myosin thick filament assembly	1	1123.5×	0.006	TTN
sarcomerogenesis	1	1123.5×	0.006	TTN
synaptic assembly at neuromuscular junction	1	1123.5×	0.006	LRP4
somatic recombination of immunoglobulin gene segments	1	842.6×	0.007	PMS2
regulation of renal sodium excretion	1	842.6×	0.007	CORIN
extraocular skeletal muscle development	1	561.7×	0.008	MYOM1
skeletal muscle thin filament assembly	1	561.7×	0.008	TTN
positive regulation of isotype switching to IgA isotypes	1	561.7×	0.008	PMS2
detection of muscle stretch	1	481.5×	0.008	TTN
postsynaptic membrane assembly	1	481.5×	0.008	LRP4
amyloid-beta clearance by cellular catabolic process	1	421.3×	0.009	LRP4
skeletal muscle acetylcholine-gated channel clustering	1	374.5×	0.009	LRP4
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	374.5×	0.009	LRP4
cardiac muscle hypertrophy	1	337.0×	0.009	TTN
presynaptic membrane assembly	1	337.0×	0.009	LRP4
positive regulation of isotype switching to IgG isotypes	1	306.4×	0.009	PMS2
generation of neurons	1	306.4×	0.009	LRP4
cardiac muscle tissue morphogenesis	1	280.9×	0.009	TTN
enzyme-linked receptor protein signaling pathway	1	259.3×	0.009	LRP4
negative regulation of axonogenesis	1	259.3×	0.009	LRP4
cardiac myofibril assembly	1	259.3×	0.009	TTN
somatic hypermutation of immunoglobulin genes	1	210.7×	0.010	PMS2
muscle filament sliding	1	210.7×	0.010	TTN
mitotic chromosome condensation	1	198.3×	0.010	TTN
peptide hormone processing	1	187.2×	0.010	CORIN

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
TTN	0	0
CORIN	0	0
TTN-AS1	0	0
LRP4	0	0
MYOM1	0	0
PMS2	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
TTN	1	Binding:1
PMS2	1	Binding:1

Cohort enzymes (BRENDA EC)

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

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	TTN, MYOM1
D	Druggable family + AlphaFold only, no drug	1	CORIN
E	Difficult family or no structure, no drug	3	TTN-AS1, LRP4, PMS2

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)
TTN	1	—
CORIN	0	—
TTN-AS1	0	—
LRP4	0	—
MYOM1	0	—
PMS2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.