dilated cardiomyopathy 1NN

Summary

dilated cardiomyopathy 1NN (MONDO:0014396) is a disease caused by RAF1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: RAF1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 42

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dilated cardiomyopathy 1NN
Mondo ID	MONDO:0014396
OMIM	615916
DOID	DOID:0110432
UMLS	C4014656
MedGen	863093
GARD	0016031
Is cancer (heuristic)	no

Also known as: cardiomyopathy, dilated, 1NN · cardiomyopathy, dilated, type 1Nn · CMD1NN · dilated cardiomyopathy type 1NN · familial isolated dilated cardiomyopathy caused by mutation in RAF1 · RAF1 familial isolated dilated cardiomyopathy

Data availability: 42 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 › dilated cardiomyopathy › familial dilated cardiomyopathy › familial isolated dilated cardiomyopathy › dilated cardiomyopathy 1NN

Related subtypes (44): dilated cardiomyopathy 1A, dilated cardiomyopathy 3B, dilated cardiomyopathy 1B, dilated cardiomyopathy 1E, dilated cardiomyopathy 1C, dilated cardiomyopathy 1D, dilated cardiomyopathy 1G, dilated cardiomyopathy 1H, dilated cardiomyopathy 1I, dilated cardiomyopathy 1K, dilated cardiomyopathy 1L, dilated cardiomyopathy 1M, dilated cardiomyopathy 1O, dilated cardiomyopathy 1P, dilated cardiomyopathy 1Q, dilated cardiomyopathy 1W, dilated cardiomyopathy 1X, dilated cardiomyopathy 1Y, dilated cardiomyopathy 1Z, dilated cardiomyopathy 2A, dilated cardiomyopathy 1AA, dilated cardiomyopathy 1BB, dilated cardiomyopathy 1CC, dilated cardiomyopathy 1DD, dilated cardiomyopathy 1EE, dilated cardiomyopathy 1FF, dilated cardiomyopathy 1R, dilated cardiomyopathy 1S, dilated cardiomyopathy 1GG, dilated cardiomyopathy 1U, dilated cardiomyopathy 1V, dilated cardiomyopathy 1HH, dilated cardiomyopathy 2B, dilated cardiomyopathy 1II, dilated cardiomyopathy 1JJ, dilated cardiomyopathy 1KK, left ventricular noncompaction 8, left ventricular noncompaction 10, cardiomyopathy, dilated, 2D, cardiomyopathy, dilated, 2E, cardiomyopathy, dilated, 2F, cardiomyopathy, dilated, 2G, cardiomyopathy, dilated, 2c, cardiomyopathy, dilated, 2H

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

42 retrieved; paginated sample, class counts are floors:

23 uncertain significance, 6 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic, 4 likely benign, 2 pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
120246	NM_002880.4(RAF1):c.782C>T (p.Pro261Leu)	RAF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13957	NM_002880.4(RAF1):c.770C>T (p.Ser257Leu)	RAF1	Pathogenic	reviewed by expert panel
142296	NM_002880.4(RAF1):c.1808T>C (p.Leu603Pro)	RAF1	Pathogenic	no assertion criteria provided
265535	NM_002880.4(RAF1):c.505G>C (p.Gly169Arg)	RAF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40605	NM_002880.4(RAF1):c.781C>G (p.Pro261Ala)	RAF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40617	NM_002880.4(RAF1):c.1423T>C (p.Phe475Leu)	RAF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496189	NM_002880.4(RAF1):c.788T>A (p.Val263Asp)	RAF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1100280	NM_002880.4(RAF1):c.192C>T (p.Asn64=)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1174673	NM_002880.4(RAF1):c.834+598G>A	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
142298	NM_002880.4(RAF1):c.1922C>T (p.Thr641Met)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
177842	NM_002880.4(RAF1):c.1721A>G (p.Tyr574Cys)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
391813	NM_002880.4(RAF1):c.1871C>G (p.Ser624Cys)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
432929	NM_002880.4(RAF1):c.601A>G (p.Ile201Val)	RAF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4278439	NM_024656.4(COLGALT1):c.566C>T (p.Ala189Val)	COLGALT1	Uncertain significance	criteria provided, single submitter
142299	NM_002880.4(RAF1):c.709G>A (p.Ala237Thr)	RAF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1675117	NM_002880.4(RAF1):c.161C>A (p.Thr54Lys)	RAF1	Uncertain significance	criteria provided, single submitter
177838	NM_002880.4(RAF1):c.-209G>A	RAF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1802975	NM_002880.4(RAF1):c.834+662G>T	RAF1	Uncertain significance	criteria provided, single submitter
1805010	NM_002880.4(RAF1):c.582-8T>G	RAF1	Uncertain significance	criteria provided, single submitter
181512	NM_002880.4(RAF1):c.1814C>T (p.Ser605Phe)	RAF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
181514	NM_002880.4(RAF1):c.1880G>A (p.Arg627Gln)	RAF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
197747	NM_002880.4(RAF1):c.438C>A (p.Phe146Leu)	RAF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2148191	NM_002880.4(RAF1):c.1483C>T (p.Arg495Cys)	RAF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
343108	NM_002880.4(RAF1):c.-181T>C	RAF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
372647	NM_002880.4(RAF1):c.482A>G (p.Asn161Ser)	RAF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3776212	NM_002880.4(RAF1):c.434_435insCTT (p.Thr145_Phe146insLeu)	RAF1	Uncertain significance	criteria provided, single submitter
393135	NM_002880.4(RAF1):c.1867C>T (p.Pro623Ser)	RAF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
40614	NM_002880.4(RAF1):c.1193G>T (p.Arg398Leu)	RAF1	Uncertain significance	reviewed by expert panel
4531293	NM_002880.4(RAF1):c.834+650A>C	RAF1	Uncertain significance	criteria provided, single submitter
517341	NM_002880.4(RAF1):c.1770G>C (p.Lys590Asn)	RAF1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 6 · 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
RAF1	Strong	Autosomal dominant	dilated cardiomyopathy 1NN	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAF1	Orphanet:154	Familial isolated dilated cardiomyopathy
RAF1	Orphanet:251615	Pilomyxoid astrocytoma
RAF1	Orphanet:500	Noonan syndrome with multiple lentigines
RAF1	Orphanet:626	Large/giant congenital melanocytic nevus
RAF1	Orphanet:648	Noonan syndrome
COLGALT1	Orphanet:99810	Familial porencephaly

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
RAF1	HGNC:9829	ENSG00000132155	P04049	RAF proto-oncogene serine/threonine-protein kinase	gencc,clinvar
COLGALT1	HGNC:26182	ENSG00000130309	Q8NBJ5	Procollagen galactosyltransferase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAF1	RAF proto-oncogene serine/threonine-protein kinase	Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including prolifer…
COLGALT1	Procollagen galactosyltransferase 1	Beta-galactosyltransferase that transfers beta-galactose to hydroxylysine residues of type I collagen.

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
Kinase	1	13.9×	0.142
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAF1	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
COLGALT1	Enzyme (other)	yes	2.4.1.50	Glyco_trans_25, Nucleotide-diphossugar_trans, Collagen_mod_GT25

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
gastrocnemius	1
muscle of leg	1
ventricular zone	1
granulocyte	1
monocyte	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAF1	299	ubiquitous	marker	gastrocnemius, muscle of leg, ventricular zone
COLGALT1	275	ubiquitous	marker	stromal cell of endometrium, granulocyte, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAF1	6,574
COLGALT1	930

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAF1	P04049	76
COLGALT1	Q8NBJ5	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
Negative feedback regulation of MAPK pathway	1	951.7×	0.006	RAF1
SHOC2 M1731 mutant abolishes MRAS complex function	1	713.8×	0.006	RAF1
Gain-of-function MRAS complexes activate RAF signaling	1	713.8×	0.006	RAF1
IFNG signaling activates MAPKs	1	713.8×	0.006	RAF1
GP1b-IX-V activation signalling	1	475.8×	0.008	RAF1
Rap1 signalling	1	356.9×	0.008	RAF1
CD209 (DC-SIGN) signaling	1	259.6×	0.009	RAF1
RAF activation	1	167.9×	0.009	RAF1
Signaling by high-kinase activity BRAF mutants	1	158.6×	0.009	RAF1
MAP2K and MAPK activation	1	142.8×	0.009	RAF1
Signaling by RAF1 mutants	1	139.3×	0.009	RAF1
Negative regulation of MAPK pathway	1	132.8×	0.009	RAF1
Signaling by moderate kinase activity BRAF mutants	1	126.9×	0.009	RAF1
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	126.9×	0.009	RAF1
Signaling downstream of RAS mutants	1	126.9×	0.009	RAF1
Collagen biosynthesis and modifying enzymes	1	85.2×	0.012	COLGALT1
Signaling by BRAF and RAF1 fusions	1	85.2×	0.012	RAF1
Stimuli-sensing channels	1	68.0×	0.015	RAF1

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
death-inducing signaling complex assembly	1	4213.0×	0.008	RAF1
positive regulation of collagen fibril organization	1	2106.5×	0.008	COLGALT1
ERBB2-ERBB3 signaling pathway	1	842.6×	0.008	RAF1
insulin secretion involved in cellular response to glucose stimulus	1	648.1×	0.008	RAF1
type II interferon-mediated signaling pathway	1	601.9×	0.008	RAF1
Schwann cell development	1	526.6×	0.008	RAF1
neurotrophin TRK receptor signaling pathway	1	526.6×	0.008	RAF1
intermediate filament cytoskeleton organization	1	468.1×	0.008	RAF1
type B pancreatic cell proliferation	1	443.5×	0.008	RAF1
face development	1	401.2×	0.008	RAF1
positive regulation of peptidyl-serine phosphorylation	1	383.0×	0.008	RAF1
response to muscle stretch	1	383.0×	0.008	RAF1
negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	1	290.6×	0.009	RAF1
thyroid gland development	1	271.8×	0.009	RAF1
regulation of Rho protein signal transduction	1	255.3×	0.009	RAF1
insulin-like growth factor receptor signaling pathway	1	247.8×	0.009	RAF1
negative regulation of protein-containing complex assembly	1	227.7×	0.009	RAF1
regulation of cell differentiation	1	216.1×	0.009	RAF1
extrinsic apoptotic signaling pathway via death domain receptors	1	200.6×	0.009	RAF1
thymus development	1	168.5×	0.010	RAF1
myelination	1	125.8×	0.012	RAF1
somatic stem cell population maintenance	1	123.9×	0.012	RAF1
wound healing	1	113.9×	0.012	RAF1
protein O-linked glycosylation	1	112.3×	0.012	COLGALT1
collagen fibril organization	1	112.3×	0.012	COLGALT1
insulin receptor signaling pathway	1	110.9×	0.012	RAF1
MAPK cascade	1	76.6×	0.017	RAF1
regulation of apoptotic process	1	41.7×	0.030	RAF1
positive regulation of MAPK cascade	1	40.3×	0.030	RAF1
protein phosphorylation	1	34.0×	0.034	RAF1

Therapeutics

Drug target analysis

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

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
RAF1	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RAF1	31	4
COLGALT1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	RAF1
SORAFENIB	4	RAF1
REGORAFENIB	4	RAF1
DABRAFENIB	4	RAF1
NILOTINIB	4	RAF1
TOVORAFENIB	4	RAF1
PAZOPANIB	4	RAF1
DASATINIB	4	RAF1
ERLOTINIB	4	RAF1
IMATINIB	4	RAF1
PLINABULIN	3	RAF1
AVUTOMETINIB	3	RAF1
NAPORAFENIB	3	RAF1
MOTESANIB	3	RAF1
DORAMAPIMOD	2	RAF1
CI-1040	2	RAF1
FORETINIB	2	RAF1
REBASTINIB	2	RAF1
TOLONIUM CHLORIDE	2	RAF1
CEP-32496	2	RAF1
BELVARAFENIB	2	RAF1
R-406	2	RAF1
RISOVALISIB	2	RAF1
EXARAFENIB	2	RAF1
RAF-265	2	RAF1
BRIMARAFENIB	2	RAF1
OSI-930	1	RAF1
PLUMBAGIN	1	RAF1
LY-3009120	1	RAF1
XP-102	1	RAF1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
RAF1	839	Binding:803, Functional:31, ADMET:5
COLGALT1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RAF1	2.7.10.2	non-specific protein-tyrosine kinase
COLGALT1	2.4.1.50	procollagen galactosyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
RAF1	839

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)
VEMURAFENIB	4	RAF1
SORAFENIB	4	RAF1
REGORAFENIB	4	RAF1
DABRAFENIB	4	RAF1
NILOTINIB	4	RAF1
TOVORAFENIB	4	RAF1
PAZOPANIB	4	RAF1
DASATINIB	4	RAF1
ERLOTINIB	4	RAF1
IMATINIB	4	RAF1
PLINABULIN	3	RAF1
AVUTOMETINIB	3	RAF1
NAPORAFENIB	3	RAF1
MOTESANIB	3	RAF1
DORAMAPIMOD	2	RAF1
CI-1040	2	RAF1
FORETINIB	2	RAF1
REBASTINIB	2	RAF1
TOLONIUM CHLORIDE	2	RAF1
CEP-32496	2	RAF1
BELVARAFENIB	2	RAF1
R-406	2	RAF1
RISOVALISIB	2	RAF1
EXARAFENIB	2	RAF1
RAF-265	2	RAF1
BRIMARAFENIB	2	RAF1
OSI-930	1	RAF1
PLUMBAGIN	1	RAF1
LY-3009120	1	RAF1
XP-102	1	RAF1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RAF1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	COLGALT1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COLGALT1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.