Hypertrophic cardiomyopathy 12

Summary

Hypertrophic cardiomyopathy 12 (MONDO:0012804) is a disease caused by CSRP3 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: CSRP3 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 400

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertrophic cardiomyopathy 12
Mondo ID	MONDO:0012804
OMIM	612124
DOID	DOID:0110318
UMLS	C2677491
MedGen	393755
GARD	0024890
Is cancer (heuristic)	no

Also known as: cardiomyopathy, familial hypertrophic, 12 · cardiomyopathy, familial hypertrophic, type 12 · cardiomyopathy, hypertrophic, 12 · CMH12 · CSRP3 hypertrophic cardiomyopathy · hypertrophic cardiomyopathy 12 · hypertrophic cardiomyopathy caused by mutation in CSRP3 · hypertrophic cardiomyopathy type 12

Data availability: 400 ClinVar variants · 2 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 12

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 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

400 retrieved; paginated sample, class counts are floors:

219 uncertain significance, 108 likely benign, 33 conflicting classifications of pathogenicity, 21 pathogenic, 8 benign/likely benign, 6 likely pathogenic, 3 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1008253	NM_003476.5(CSRP3):c.377C>G (p.Ser126Ter)	CSRP3	Pathogenic	criteria provided, single submitter
1009234	NM_003476.5(CSRP3):c.49_55del (p.Val17fs)	CSRP3	Pathogenic	criteria provided, single submitter
1011003	NM_003476.5(CSRP3):c.72del (p.Gln24fs)	CSRP3	Pathogenic	criteria provided, single submitter
1324182	NM_003476.5(CSRP3):c.50_51insGCAGATTTCTT (p.Tyr18fs)	CSRP3	Pathogenic	criteria provided, multiple submitters, no conflicts
1418855	NM_003476.5(CSRP3):c.82_85del (p.Arg28fs)	CSRP3	Pathogenic	criteria provided, single submitter
1470431	NM_003476.5(CSRP3):c.165del (p.Ile56fs)	CSRP3	Pathogenic	criteria provided, single submitter
216572	NM_003476.5(CSRP3):c.337A>T (p.Lys113Ter)	CSRP3	Pathogenic	criteria provided, single submitter
219444	NM_003476.5(CSRP3):c.449G>A (p.Cys150Tyr)	CSRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2932324	NM_003476.5(CSRP3):c.186T>G (p.Tyr62Ter)	CSRP3	Pathogenic	criteria provided, single submitter
2951005	NM_003476.5(CSRP3):c.279del (p.Gln93fs)	CSRP3	Pathogenic	criteria provided, single submitter
3244681	NC_000011.9:g.(?18418390)(19213995_?)del	CSRP3	Pathogenic	criteria provided, single submitter
372584	NM_003476.5(CSRP3):c.364C>T (p.Arg122Ter)	CSRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3752686	NM_003476.5(CSRP3):c.444dup (p.Ile149fs)	CSRP3	Pathogenic	criteria provided, single submitter
3755823	NM_003476.5(CSRP3):c.304del (p.Val102fs)	CSRP3	Pathogenic	criteria provided, single submitter
3759643	NM_003476.5(CSRP3):c.54C>A (p.Tyr18Ter)	CSRP3	Pathogenic	criteria provided, single submitter
3764079	NM_003476.5(CSRP3):c.27del (p.Lys9fs)	CSRP3	Pathogenic	criteria provided, single submitter
4784477	NM_003476.5(CSRP3):c.161C>A (p.Ser54Ter)	CSRP3	Pathogenic	criteria provided, single submitter
4786672	NM_003476.5(CSRP3):c.298del (p.Arg100fs)	CSRP3	Pathogenic	criteria provided, single submitter
543041	NM_003476.5(CSRP3):c.55del (p.His19fs)	CSRP3	Pathogenic	criteria provided, single submitter
543042	NM_003476.5(CSRP3):c.373A>T (p.Lys125Ter)	CSRP3	Pathogenic	criteria provided, single submitter
655718	NM_003476.5(CSRP3):c.52del (p.Tyr18fs)	CSRP3	Pathogenic	criteria provided, single submitter
8777	NM_003476.5(CSRP3):c.172T>G (p.Cys58Gly)	CSRP3	Pathogenic	criteria provided, multiple submitters, no conflicts
8779	NM_003476.5(CSRP3):c.160_164delinsAGGGG (p.Ser54_Glu55delinsArgGly)	CSRP3	Pathogenic	no assertion criteria provided
915721	NM_003476.5(CSRP3):c.111C>A (p.Cys37Ter)	CSRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4845268	NM_020778.5(ALPK3):c.3301_3316dup (p.Ser1106fs)	ALPK3	Likely pathogenic	no assertion criteria provided
2941886	NM_003476.5(CSRP3):c.281+2T>C	CSRP3	Likely pathogenic	criteria provided, single submitter
2947685	NM_003476.5(CSRP3):c.414+1G>A	CSRP3	Likely pathogenic	criteria provided, single submitter
3763020	NM_003476.5(CSRP3):c.414+1G>C	CSRP3	Likely pathogenic	criteria provided, single submitter
4791293	NM_003476.5(CSRP3):c.281+1G>C	CSRP3	Likely pathogenic	criteria provided, single submitter
915578	NM_003476.5(CSRP3):c.414+1G>T	CSRP3	Likely pathogenic	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
CSRP3	Strong	Autosomal dominant	hypertrophic cardiomyopathy 12	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CSRP3	Orphanet:154	Familial isolated dilated cardiomyopathy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CSRP3	HGNC:2472	ENSG00000129170	P50461	Cysteine and glycine-rich protein 3	gencc,clinvar
ALPK3	HGNC:17574	ENSG00000136383	Q96L96	Alpha-protein kinase 3	clinvar
LDHAL6A	HGNC:28335	ENSG00000166800	Q6ZMR3	L-lactate dehydrogenase A-like 6A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CSRP3	Cysteine and glycine-rich protein 3	Positive regulator of myogenesis.
ALPK3	Alpha-protein kinase 3	Involved in cardiomyocyte differentiation.
LDHAL6A	L-lactate dehydrogenase A-like 6A	Catalyzes the interconversion of L-lactate and pyruvate with nicotinamide adenine dinucleotide NAD(+) as a coenzyme.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · 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
Kinase	1	9.2×	0.313
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CSRP3	Transcription factor	no		Znf_LIM
ALPK3	Kinase	yes		Ig_sub2, Ig_sub, a-kinase_dom
LDHAL6A	Other/Unknown	no		Lactate/malate_DH_N, L-lactate/malate_DH, L-lactate_DH

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
heart right ventricle	1
left ventricle myocardium	1
skeletal muscle tissue of rectus abdominis	1
gastrocnemius	1
gluteal muscle	1
hindlimb stylopod muscle	1
male germ line stem cell (sensu Vertebrata) in testis	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CSRP3	173	tissue_specific	marker	skeletal muscle tissue of rectus abdominis, heart right ventricle, left ventricle myocardium
ALPK3	201	broad	yes	gastrocnemius, hindlimb stylopod muscle, gluteal muscle
LDHAL6A	134	tissue_specific	yes	secondary oocyte, oocyte, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LDHAL6A	3,097
CSRP3	1,376
ALPK3	878

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CSRP3	P50461	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LDHAL6A	Q6ZMR3	95.39
ALPK3	Q96L96	49.15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 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
Pyruvate metabolism	1	407.9×	0.007	LDHAL6A
Aerobic respiration and respiratory electron transport	1	88.5×	0.017	LDHAL6A
Metabolism	1	11.6×	0.086	LDHAL6A

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of actin filament severing	1	5617.3×	0.005	CSRP3
negative regulation of actin filament severing	1	2808.7×	0.005	CSRP3
muscle tissue development	1	1123.5×	0.005	CSRP3
T-tubule organization	1	936.2×	0.005	CSRP3
phospholipase C/protein kinase C signal transduction	1	936.2×	0.005	CSRP3
detection of muscle stretch	1	802.5×	0.005	CSRP3
pyruvate catabolic process	1	702.2×	0.005	LDHAL6A
lactate metabolic process	1	624.1×	0.005	LDHAL6A
establishment of protein localization to organelle	1	624.1×	0.005	CSRP3
cardiac muscle hypertrophy	1	561.7×	0.005	CSRP3
cardiac myofibril assembly	1	432.1×	0.006	CSRP3
regulation of the force of heart contraction	1	330.4×	0.007	CSRP3
cardiac muscle tissue development	1	295.6×	0.007	CSRP3
muscle cell cellular homeostasis	1	216.1×	0.008	CSRP3
regulation of protein localization to plasma membrane	1	216.1×	0.008	CSRP3
negative regulation of myoblast differentiation	1	208.1×	0.008	CSRP3
cardiac muscle cell development	1	208.1×	0.008	ALPK3
cardiac muscle contraction	1	133.8×	0.011	CSRP3
sarcomere organization	1	127.7×	0.011	CSRP3
positive regulation of myoblast differentiation	1	122.1×	0.011	CSRP3
skeletal muscle tissue development	1	96.8×	0.013	CSRP3
insulin receptor signaling pathway	1	73.9×	0.017	CSRP3
intracellular calcium ion homeostasis	1	48.4×	0.024	CSRP3
glucose homeostasis	1	43.5×	0.026	CSRP3
heart development	1	26.2×	0.041	ALPK3
inflammatory response	1	12.6×	0.080	CSRP3
positive regulation of transcription by RNA polymerase II	1	5.0×	0.188	CSRP3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 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
CSRP3	0	0
ALPK3	0	0
LDHAL6A	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
ALPK3	10	Binding:10

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	ALPK3
E	Difficult family or no structure, no drug	2	CSRP3, LDHAL6A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CSRP3	0	—
ALPK3	10	—
LDHAL6A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.