Hypertrophic cardiomyopathy 8

Summary

Hypertrophic cardiomyopathy 8 (MONDO:0012111) is a disease caused by MYL3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: MYL3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 56

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertrophic cardiomyopathy 8
Mondo ID	MONDO:0012111
MeSH	C563866
OMIM	608751
DOID	DOID:0110314
UMLS	C1837471
MedGen	324806
GARD	0024842
Is cancer (heuristic)	no

Also known as: cardiomyopathy, familial hypertrophic, 8 · cardiomyopathy, familial hypertrophic, type 8 · cardiomyopathy, hypertrophic, 8 · CMH8 · hypertrophic cardiomyopathy 8 · hypertrophic cardiomyopathy caused by mutation in MYL3 · hypertrophic cardiomyopathy type 8 · MYL3 hypertrophic cardiomyopathy

Data availability: 56 ClinVar variants · 3 GenCC gene-disease records.

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 8

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 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 9, 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

56 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 14 conflicting classifications of pathogenicity, 5 benign/likely benign, 4 benign, 2 likely benign, 2 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14061	NM_000258.3(MYL3):c.445A>G (p.Met149Val)	MYL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31777	NM_000258.3(MYL3):c.281G>A (p.Arg94His)	MYL3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4280110	NM_001079668.3(NKX2-1):c.824del (p.Pro275fs)	NKX2-1	Likely pathogenic	criteria provided, single submitter
1517630	NM_000258.3(MYL3):c.157+1G>A	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
164491	NM_000258.3(MYL3):c.4G>C (p.Ala2Pro)	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
177841	NM_000258.3(MYL3):c.466G>T (p.Val156Leu)	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
179888	NM_000258.3(MYL3):c.*5C>T	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
181441	NM_000258.3(MYL3):c.220G>A (p.Gly74Arg)	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
227621	NM_000258.3(MYL3):c.307+15C>T	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
228936	NM_000258.3(MYL3):c.92G>A (p.Arg31His)	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
31778	NM_000258.3(MYL3):c.466G>A (p.Val156Met)	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
31783	NM_000258.3(MYL3):c.463C>G (p.His155Asp)	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
345570	NM_000258.3(MYL3):c.219C>T (p.Tyr73=)	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
345571	NM_000258.3(MYL3):c.96T>A (p.Pro32=)	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43123	NM_000258.3(MYL3):c.446T>C (p.Met149Thr)	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43128	NM_000258.3(MYL3):c.532G>A (p.Asp178Asn)	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43130	NM_000258.3(MYL3):c.81T>C (p.Pro27=)	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1011968	NM_000258.3(MYL3):c.308-3C>T	MYL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1172131	NM_000258.3(MYL3):c.557A>C (p.Glu186Ala)	MYL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1402380	NM_000258.3(MYL3):c.158-2A>G	MYL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
14062	NM_000258.3(MYL3):c.461G>A (p.Arg154His)	MYL3	Uncertain significance	reviewed by expert panel
14063	NM_000258.3(MYL3):c.427G>A (p.Glu143Lys)	MYL3	Uncertain significance	reviewed by expert panel
161329	NM_000258.3(MYL3):c.235G>A (p.Val79Ile)	MYL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1809684	NM_000258.3(MYL3):c.*13G>A	MYL3	Uncertain significance	criteria provided, single submitter
31779	NM_000258.3(MYL3):c.517A>G (p.Met173Val)	MYL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
31780	NM_000258.3(MYL3):c.170C>G (p.Ala57Gly)	MYL3	Uncertain significance	reviewed by expert panel
36648	NM_000258.3(MYL3):c.530A>G (p.Glu177Gly)	MYL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
426252	NM_000258.3(MYL3):c.449G>A (p.Gly150Asp)	MYL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
426762	NM_000258.3(MYL3):c.152T>C (p.Ile51Thr)	MYL3	Uncertain significance	criteria provided, multiple submitters, no conflicts
43121	NM_000258.3(MYL3):c.170C>A (p.Ala57Asp)	MYL3	Uncertain significance	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 4 · 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
MYL3	Definitive	Autosomal dominant	hypertrophic cardiomyopathy	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NKX2-1	Orphanet:1429	Benign hereditary chorea
NKX2-1	Orphanet:146	Differentiated thyroid carcinoma
NKX2-1	Orphanet:209905	Brain-lung-thyroid syndrome
NKX2-1	Orphanet:95713	Athyreosis

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
MYL3	HGNC:7584	ENSG00000160808	P08590	Myosin light chain 3	gencc,clinvar
NKX2-1	HGNC:11825	ENSG00000136352	P43699	Homeobox protein Nkx-2.1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYL3	Myosin light chain 3	Regulatory light chain of myosin.
NKX2-1	Homeobox protein Nkx-2.1	Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYL3	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, CALM/Myosin/TropC-like
NKX2-1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS

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
apex of heart	1
heart right ventricle	1
hindlimb stylopod muscle	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYL3	198	broad	marker	apex of heart, heart right ventricle, hindlimb stylopod muscle
NKX2-1	101	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NKX2-1	2,403
MYL3	2,255

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYL3	P08590	3
NKX2-1	P43699	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Striated Muscle Contraction	1	308.6×	0.006	MYL3
Muscle contraction	1	77.2×	0.013	MYL3

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
developmental induction	1	4213.0×	0.005	NKX2-1
cerebral cortex GABAergic interneuron differentiation	1	2808.7×	0.005	NKX2-1
globus pallidus development	1	1685.2×	0.005	NKX2-1
forebrain neuron fate commitment	1	1685.2×	0.005	NKX2-1
club cell differentiation	1	1685.2×	0.005	NKX2-1
regulation of striated muscle contraction	1	1053.2×	0.005	MYL3
forebrain dorsal/ventral pattern formation	1	1053.2×	0.005	NKX2-1
lung saccule development	1	1053.2×	0.005	NKX2-1
type II pneumocyte differentiation	1	1053.2×	0.005	NKX2-1
anatomical structure formation involved in morphogenesis	1	936.2×	0.005	NKX2-1
cerebral cortex cell migration	1	766.0×	0.005	NKX2-1
interneuron migration	1	766.0×	0.005	NKX2-1
Leydig cell differentiation	1	601.9×	0.005	NKX2-1
positive regulation of circadian rhythm	1	601.9×	0.005	NKX2-1
hypothalamus development	1	526.6×	0.006	NKX2-1
regulation of the force of heart contraction	1	495.6×	0.006	MYL3
epithelial tube branching involved in lung morphogenesis	1	421.3×	0.006	NKX2-1
ventricular cardiac muscle tissue morphogenesis	1	351.1×	0.007	MYL3
pituitary gland development	1	324.1×	0.007	NKX2-1
endoderm development	1	312.1×	0.007	NKX2-1
thyroid gland development	1	271.8×	0.008	NKX2-1
response to hormone	1	216.1×	0.009	NKX2-1
oligodendrocyte differentiation	1	210.7×	0.009	NKX2-1
negative regulation of epithelial to mesenchymal transition	1	205.5×	0.009	NKX2-1
cardiac muscle contraction	1	200.6×	0.009	MYL3
forebrain development	1	175.5×	0.010	NKX2-1
phospholipid metabolic process	1	172.0×	0.010	NKX2-1
skeletal muscle tissue development	1	145.3×	0.011	MYL3
rhythmic process	1	125.8×	0.013	NKX2-1
hippocampus development	1	115.4×	0.013	NKX2-1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYL3	0	0
NKX2-1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MYL3, NKX2-1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MYL3	0	—
NKX2-1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.