Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy

Summary

Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy (MONDO:0859168) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy
Mondo ID	MONDO:0859168
OMIM	619424
DOID	DOID:0051044
UMLS	C5561937
MedGen	1794147
GARD	0026661
Is cancer (heuristic)	no

Data availability: 24 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 › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › myofibrillar myopathy › myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy

Related subtypes (12): central core myopathy, myofibrillar myopathy 1, myofibrillar myopathy 3, myofibrillar myopathy 4, myofibrillar myopathy 5, myofibrillar myopathy 6, fatal infantile hypertonic myofibrillar myopathy, myofibrillar myopathy 7, myofibrillar myopathy 8, myofibrillar myopathy 11, myofibrillar myopathy 10, myopathy, myofibrillar, 13, with rimmed vacuoles

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

24 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 7 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
14068	NM_000432.4(MYL2):c.52T>C (p.Phe18Leu)	LOC114827850	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
944169	NM_000432.4(MYL2):c.51_61del (p.Phe18fs)	LOC114827850	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1297593	NM_000432.4(MYL2):c.376C>T (p.Gln126Ter)	MYL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
31766	NM_000432.4(MYL2):c.141C>A (p.Asn47Lys)	MYL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
31768	NM_000432.4(MYL2):c.403-1G>C	MYL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
36645	NM_000432.4(MYL2):c.359G>A (p.Arg120Gln)	MYL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
43475	NM_000432.4(MYL2):c.401A>C (p.Glu134Ala)	MYL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
626790	NM_000432.4(MYL2):c.431_432del (p.Pro144fs)	MYL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4278185	NM_012087.4(GTF3C5):c.803C>T (p.Ala268Val)	GTF3C5	Uncertain significance	criteria provided, single submitter
1387258	NM_000432.4(MYL2):c.50T>C (p.Val17Ala)	LOC114827850	Uncertain significance	criteria provided, multiple submitters, no conflicts
181424	NM_000432.4(MYL2):c.49G>A (p.Val17Met)	LOC114827850	Uncertain significance	criteria provided, multiple submitters, no conflicts
1043372	NM_000432.4(MYL2):c.432del (p.Asp145fs)	MYL2	Uncertain significance	criteria provided, single submitter
177824	NM_000432.4(MYL2):c.428C>T (p.Pro143Leu)	MYL2	Uncertain significance	reviewed by expert panel
181427	NM_000432.4(MYL2):c.97T>C (p.Phe33Leu)	MYL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
181434	NM_000432.4(MYL2):c.358C>G (p.Arg120Gly)	MYL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
191580	NM_000432.4(MYL2):c.431del (p.Pro144fs)	MYL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
423350	NM_000432.4(MYL2):c.376C>G (p.Gln126Glu)	MYL2	Uncertain significance	reviewed by expert panel
450755	NM_000432.4(MYL2):c.366G>T (p.Met122Ile)	MYL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
567448	NM_000432.4(MYL2):c.203A>G (p.Glu68Gly)	MYL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
654375	NM_000432.4(MYL2):c.142G>A (p.Asp48Asn)	MYL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
884050	NM_000432.4(MYL2):c.*84C>T	MYL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
927979	NM_000432.4(MYL2):c.206T>C (p.Met69Thr)	MYL2	Uncertain significance	criteria provided, multiple submitters, no conflicts
31772	NM_000432.4(MYL2):c.353+20del	MYL2	Benign	criteria provided, multiple submitters, no conflicts
464145	NM_000432.4(MYL2):c.375G>A (p.Thr125=)	MYL2	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
MYL2	Definitive	Autosomal dominant	hypertrophic cardiomyopathy 10	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYL2	Orphanet:2020	Congenital fiber-type disproportion myopathy

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
MYL2	HGNC:7583	ENSG00000111245	P10916	Myosin regulatory light chain 2, ventricular/cardiac muscle isoform	gencc,clinvar
GTF3C5	HGNC:4668	ENSG00000148308	Q9Y5Q8	General transcription factor 3C polypeptide 5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYL2	Myosin regulatory light chain 2, ventricular/cardiac muscle isoform	Contractile protein that plays a role in heart development and function.
GTF3C5	General transcription factor 3C polypeptide 5	Involved in RNA polymerase III-mediated transcription.

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)
MYL2	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
GTF3C5	Transcription factor	no		TF_IIIC_su-5_HTH, TF_IIIC_Tfc1/Sfc1, Tfc1/Sfc1_N

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
diaphragm	1
heart right ventricle	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYL2	179	tissue_specific	marker	heart right ventricle, diaphragm, apex of heart
GTF3C5	252	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYL2	3,119
GTF3C5	1,933

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYL2	P10916	3
GTF3C5	Q9Y5Q8	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	211.5×	0.010	GTF3C5
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	203.9×	0.010	GTF3C5
RNA Polymerase III Transcription Initiation	1	167.9×	0.010	GTF3C5
RNA Polymerase III Transcription	1	163.1×	0.010	GTF3C5
Striated Muscle Contraction	1	154.3×	0.010	MYL2
RNA Polymerase III Abortive And Retractive Initiation	1	139.3×	0.010	GTF3C5
Muscle contraction	1	38.6×	0.029	MYL2
Gene expression (Transcription)	1	8.9×	0.109	GTF3C5

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
muscle cell fate specification	1	8426.0×	0.002	MYL2
positive regulation of the force of heart contraction	1	1685.2×	0.003	MYL2
5S class rRNA transcription by RNA polymerase III	1	1404.3×	0.003	GTF3C5
transcription initiation at RNA polymerase III promoter	1	1203.7×	0.003	GTF3C5
regulation of striated muscle contraction	1	1053.2×	0.003	MYL2
tRNA transcription by RNA polymerase III	1	766.0×	0.003	GTF3C5
cardiac myofibril assembly	1	648.1×	0.004	MYL2
regulation of the force of heart contraction	1	495.6×	0.004	MYL2
transcription by RNA polymerase III	1	383.0×	0.004	GTF3C5
heart contraction	1	383.0×	0.004	MYL2
ventricular cardiac muscle tissue morphogenesis	1	351.1×	0.004	MYL2
cardiac muscle contraction	1	200.6×	0.007	MYL2
skeletal muscle cell differentiation	1	172.0×	0.007	GTF3C5
post-embryonic development	1	102.8×	0.011	MYL2
negative regulation of cell growth	1	72.0×	0.015	MYL2
heart development	1	39.4×	0.025	MYL2

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYL2	0	0
GTF3C5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GTF3C5	1	Binding:1

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	MYL2, GTF3C5

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)
MYL2	0	—
GTF3C5	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.