dilated cardiomyopathy 1U

Summary

dilated cardiomyopathy 1U (MONDO:0013371) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 131

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dilated cardiomyopathy 1U
Mondo ID	MONDO:0013371
MeSH	C566296
OMIM	613694
DOID	DOID:0110455
UMLS	C3160720
MedGen	463620
GARD	0015689
Is cancer (heuristic)	no

Also known as: cardiomyopathy, dilated, 1U · cardiomyopathy, dilated, type 1U · CMD1U · dilated cardiomyopathy type 1U · familial isolated dilated cardiomyopathy caused by mutation in PSEN1 · PSEN1 familial isolated dilated cardiomyopathy

Data availability: 131 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 › dilated cardiomyopathy › familial dilated cardiomyopathy › familial isolated dilated cardiomyopathy › dilated cardiomyopathy 1U

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 1V, dilated cardiomyopathy 1HH, dilated cardiomyopathy 2B, dilated cardiomyopathy 1II, dilated cardiomyopathy 1JJ, dilated cardiomyopathy 1KK, left ventricular noncompaction 8, left ventricular noncompaction 10, dilated cardiomyopathy 1NN, 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

131 retrieved; paginated sample, class counts are floors:

72 uncertain significance, 29 conflicting classifications of pathogenicity, 20 benign/likely benign, 5 benign, 3 pathogenic, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
18124	NM_000021.4(PSEN1):c.488A>G (p.His163Arg)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18136	NM_000021.4(PSEN1):c.1276G>C (p.Ala426Pro)	PSEN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18143	NM_000021.4(PSEN1):c.617G>C (p.Gly206Ala)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
18155	NM_000021.4(PSEN1):c.1292C>A (p.Ala431Glu)	PSEN1	Pathogenic	criteria provided, multiple submitters, no conflicts
98065	NM_000021.4(PSEN1):c.691G>A (p.Ala231Thr)	PSEN1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1798669	NM_000258.3(MYL3):c.2T>A (p.Met1Lys)	MYL3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1518360	NM_000021.4(PSEN1):c.1377A>G (p.Gln459=)	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18156	NM_000021.4(PSEN1):c.998A>G (p.Asp333Gly)	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
254713	NM_000021.4(PSEN1):c.1017A>G (p.Glu339=)	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313944	NM_000021.4(PSEN1):c.21G>A (p.Pro7=)	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313946	NM_000021.4(PSEN1):c.337C>T (p.Leu113=)	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313947	NM_000021.4(PSEN1):c.654A>G (p.Pro218=)	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313948	NM_000021.4(PSEN1):c.1002C>T (p.Gly334=)	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313958	NM_000021.4(PSEN1):c.*672G>A	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313965	NM_000021.4(PSEN1):c.*1381G>A	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313978	NM_000021.4(PSEN1):c.*2108G>A	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313985	NM_000021.4(PSEN1):c.*2529G>T	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313995	NM_000021.4(PSEN1):c.*3495A>G	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314004	NM_000021.4(PSEN1):c.*3941C>A	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
599627	NM_000021.4(PSEN1):c.424G>A (p.Val142Ile)	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
707810	NM_000021.4(PSEN1):c.234C>T (p.Gly78=)	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
723135	NM_000021.4(PSEN1):c.792G>T (p.Pro264=)	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884412	NM_000021.4(PSEN1):c.843G>A (p.Thr281=)	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884666	NM_000021.4(PSEN1):c.*2543C>T	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884667	NM_000021.4(PSEN1):c.*2580C>T	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884729	NM_000021.4(PSEN1):c.*3328C>G	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885669	NM_000021.4(PSEN1):c.*3508G>A	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
885730	NM_000021.4(PSEN1):c.*4113G>A	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
886494	NM_000021.4(PSEN1):c.*1484A>C	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
886561	NM_000021.4(PSEN1):c.*2017A>T	PSEN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 5 · 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
PSEN1	Supportive	Autosomal dominant	familial isolated dilated cardiomyopathy	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PSEN1	Orphanet:100069	Semantic dementia
PSEN1	Orphanet:100070	Progressive non-fluent aphasia
PSEN1	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
PSEN1	Orphanet:154	Familial isolated dilated cardiomyopathy
PSEN1	Orphanet:275864	Behavioral variant of frontotemporal dementia

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
PSEN1	HGNC:9508	ENSG00000080815	P49768	Presenilin-1	gencc,clinvar
MYL3	HGNC:7584	ENSG00000160808	P08590	Myosin light chain 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PSEN1	Presenilin-1	Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein).
MYL3	Myosin light chain 3	Regulatory light chain of myosin.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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	18.3×	0.108
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSEN1	Protease	yes		Peptidase_A22A, Pept_A22A_PS1, Preselin/SPP
MYL3	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, CALM/Myosin/TropC-like

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
C1 segment of cervical spinal cord	1
corpus callosum	1
middle frontal gyrus	1
apex of heart	1
heart right ventricle	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSEN1	287	ubiquitous	marker	middle frontal gyrus, corpus callosum, C1 segment of cervical spinal cord
MYL3	198	broad	marker	apex of heart, heart right ventricle, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSEN1	3,732
MYL3	2,255

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSEN1	P49768	27
MYL3	P08590	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Noncanonical activation of NOTCH3	1	713.8×	0.008	PSEN1
Regulated proteolysis of p75NTR	1	519.1×	0.008	PSEN1
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	519.1×	0.008	PSEN1
TGFBR3 PTM regulation	1	475.8×	0.008	PSEN1
NRIF signals cell death from the nucleus	1	356.9×	0.009	PSEN1
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	237.9×	0.010	PSEN1
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	219.6×	0.010	PSEN1
Activated NOTCH1 Transmits Signal to the Nucleus	1	178.4×	0.010	PSEN1
Nuclear signaling by ERBB4	1	173.0×	0.010	PSEN1
Striated Muscle Contraction	1	154.3×	0.010	MYL3
EPH-ephrin mediated repulsion of cells	1	109.8×	0.012	PSEN1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	98.5×	0.012	PSEN1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	98.5×	0.012	PSEN1
Degradation of the extracellular matrix	1	58.9×	0.019	PSEN1
Muscle contraction	1	38.6×	0.027	MYL3
Neutrophil degranulation	1	11.5×	0.085	PSEN1

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
positive regulation of L-glutamate import across plasma membrane	1	4213.0×	0.006	PSEN1
Cajal-Retzius cell differentiation	1	4213.0×	0.006	PSEN1
smooth endoplasmic reticulum calcium ion homeostasis	1	4213.0×	0.006	PSEN1
protein catabolic process at postsynapse	1	2808.7×	0.006	PSEN1
astrocyte activation involved in immune response	1	2106.5×	0.006	PSEN1
obsolete synaptic vesicle targeting	1	2106.5×	0.006	PSEN1
obsolete sequestering of calcium ion	1	1685.2×	0.006	PSEN1
positive regulation of amyloid fibril formation	1	1685.2×	0.006	PSEN1
positive regulation of coagulation	1	1404.3×	0.006	PSEN1
regulation of striated muscle contraction	1	1053.2×	0.006	MYL3
Notch receptor processing	1	936.2×	0.006	PSEN1
amyloid-beta formation	1	936.2×	0.006	PSEN1
L-glutamate import across plasma membrane	1	936.2×	0.006	PSEN1
choline transport	1	766.0×	0.006	PSEN1
cerebral cortex cell migration	1	766.0×	0.006	PSEN1
locomotion	1	766.0×	0.006	PSEN1
skin morphogenesis	1	702.2×	0.006	PSEN1
amyloid precursor protein metabolic process	1	648.1×	0.006	PSEN1
negative regulation of axonogenesis	1	648.1×	0.006	PSEN1
regulation of resting membrane potential	1	648.1×	0.006	PSEN1
mitochondrial transport	1	601.9×	0.006	PSEN1
amyloid precursor protein catabolic process	1	601.9×	0.006	PSEN1
positive regulation of receptor recycling	1	561.7×	0.006	PSEN1
regulation of synaptic vesicle cycle	1	561.7×	0.006	PSEN1
neuron projection maintenance	1	561.7×	0.006	PSEN1
regulation of the force of heart contraction	1	495.6×	0.006	MYL3
astrocyte activation	1	495.6×	0.006	PSEN1
neural retina development	1	468.1×	0.006	PSEN1
myeloid dendritic cell differentiation	1	468.1×	0.006	PSEN1
endoplasmic reticulum calcium ion homeostasis	1	421.3×	0.007	PSEN1

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
PSEN1	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSEN1	8	4
MYL3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIROGACESTAT	4	PSEN1
TARENFLURBIL	3	PSEN1
SEMAGACESTAT	3	PSEN1
AVAGACESTAT	2	PSEN1
RG-4733	2	PSEN1
BEGACESTAT	2	PSEN1
E-2212	1	PSEN1
MK-0752	1	PSEN1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PSEN1	557	Binding:538, Functional:12, ADMET:6, Unclassified:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PSEN1	557

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

8 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)
NIROGACESTAT	4	PSEN1
TARENFLURBIL	3	PSEN1
SEMAGACESTAT	3	PSEN1
AVAGACESTAT	2	PSEN1
RG-4733	2	PSEN1
BEGACESTAT	2	PSEN1
E-2212	1	PSEN1
MK-0752	1	PSEN1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSEN1
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	1	MYL3

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)
MYL3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.