Restrictive dermopathy 2

Summary

Restrictive dermopathy 2 (MONDO:0030781) is a disease caused by LMNA (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: LMNA (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 189

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	restrictive dermopathy 2
Mondo ID	MONDO:0030781
OMIM	619793
DOID	DOID:0070370
UMLS	C5676942
MedGen	1801155
GARD	0025636
Is cancer (heuristic)	no

Also known as: restrictive dermopathy 2 · restrictive dermopathy 2, lethal · RSDM2

Data availability: 189 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › restrictive dermopathy › restrictive dermopathy 2

Related subtypes (1): restrictive dermopathy 1

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

189 retrieved; paginated sample, class counts are floors:

98 uncertain significance, 52 conflicting classifications of pathogenicity, 17 likely benign, 7 pathogenic/likely pathogenic, 6 pathogenic, 6 benign/likely benign, 1 likely pathogenic, 1 benign, 1 uncertain significance/uncertain risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
14489	NM_170707.4(LMNA):c.1444C>T (p.Arg482Trp)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14495	NM_170707.4(LMNA):c.1130G>A (p.Arg377His)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
14500	NM_170707.4(LMNA):c.1824C>T (p.Gly608=)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
1457399	NM_170707.4(LMNA):c.822del (p.Arg275fs)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200941	NM_170707.4(LMNA):c.768G>A (p.Val256=)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3595598	NM_170707.4(LMNA):c.5del (p.Glu2fs)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
36473	NM_170707.4(LMNA):c.1003C>T (p.Arg335Trp)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
48096	NM_170707.4(LMNA):c.961C>T (p.Arg321Ter)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
66762	NM_170707.4(LMNA):c.1045C>T (p.Arg349Trp)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66800	NM_170707.4(LMNA):c.1294C>T (p.Gln432Ter)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66853	NM_170707.4(LMNA):c.1608+1G>A	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
66879	NM_170707.4(LMNA):c.1968+1G>A	LMNA	Pathogenic	no assertion criteria provided
66931	NM_170707.4(LMNA):c.746G>A (p.Arg249Gln)	LMNA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343751	NM_170707.4(LMNA):c.1646_1647del (p.Val549fs)	LMNA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
48078	NM_170707.4(LMNA):c.749C>T (p.Ala250Val)	LMNA	Uncertain significance/Uncertain risk allele	criteria provided, multiple submitters, no conflicts
1029259	NM_170707.4(LMNA):c.187A>C (p.Ile63Leu)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1284657	NM_170707.4(LMNA):c.1786_1800del (p.Asp596_Ala600del)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14494	NM_170707.4(LMNA):c.1745G>A (p.Arg582His)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14498	NM_170707.4(LMNA):c.892C>T (p.Arg298Cys)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14499	NM_170707.4(LMNA):c.1580G>A (p.Arg527His)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14517	NM_170707.4(LMNA):c.1718C>T (p.Ser573Leu)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14519	NM_170707.4(LMNA):c.1195C>T (p.Arg399Cys)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14520	NM_170707.4(LMNA):c.1318G>A (p.Val440Met)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14527	NM_170707.4(LMNA):c.1930C>T (p.Arg644Cys)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1501721	NM_170707.4(LMNA):c.11C>A (p.Pro4Gln)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1518015	NM_170707.4(LMNA):c.244G>C (p.Glu82Gln)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
161291	NM_170707.4(LMNA):c.1931G>A (p.Arg644His)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
163878	NM_170707.4(LMNA):c.1634G>A (p.Arg545His)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1750607	NM_170707.4(LMNA):c.593A>G (p.Gln198Arg)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
178062	NM_170707.4(LMNA):c.1376A>G (p.Asn459Ser)	LMNA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 40 · Orphanet: 21 · 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
LMNA	Definitive	Autosomal recessive	restrictive dermopathy 2	40

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LMNA	Orphanet:154	Familial isolated dilated cardiomyopathy
LMNA	Orphanet:157973	Congenital muscular dystrophy due to LMNA mutation
LMNA	Orphanet:1662	Restrictive dermopathy
LMNA	Orphanet:168796	Heart-hand syndrome, Slovenian type
LMNA	Orphanet:2229	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
LMNA	Orphanet:2348	Familial partial lipodystrophy, Dunnigan type
LMNA	Orphanet:280365	Autosomal semi-dominant severe lipodystrophic laminopathy
LMNA	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LMNA	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LMNA	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LMNA	Orphanet:300751	Familial dilated cardiomyopathy with conduction defect due to LMNA mutation
LMNA	Orphanet:363618	LMNA-related cardiocutaneous progeria syndrome
LMNA	Orphanet:54260	Left ventricular noncompaction
LMNA	Orphanet:675396	Epithelioid hemangioma
LMNA	Orphanet:740	Hutchinson-Gilford progeria syndrome
LMNA	Orphanet:79084	Familial partial lipodystrophy, Köbberling type
LMNA	Orphanet:79474	Atypical Werner syndrome
LMNA	Orphanet:90153	Mandibuloacral dysplasia with type A lipodystrophy
LMNA	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98855	Autosomal recessive Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98856	Charcot-Marie-Tooth disease type 2B1

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LMNA	Prelamin-A/C	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of stomach	1
nipple	1
skin of abdomen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNA	7,173

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LMNA	P02545	28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 1 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
Breakdown of the nuclear lamina	1	3806.7×	0.004	LMNA
Depolymerization of the Nuclear Lamina	1	761.3×	0.005	LMNA
Initiation of Nuclear Envelope (NE) Reformation	1	601.0×	0.005	LMNA
IRE1alpha activates chaperones	1	519.1×	0.005	LMNA
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	519.1×	0.005	LMNA
Nuclear Envelope Breakdown	1	456.8×	0.005	LMNA
Unfolded Protein Response (UPR)	1	356.9×	0.006	LMNA
Oncogenic MAPK signaling	1	248.3×	0.008	LMNA
XBP1(S) activates chaperone genes	1	215.5×	0.008	LMNA
Signaling by BRAF and RAF1 fusions	1	170.4×	0.009	LMNA
Meiotic synapsis	1	141.0×	0.010	LMNA
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.022	LMNA
Cellular responses to stress	1	36.8×	0.031	LMNA
Cellular responses to stimuli	1	31.5×	0.034	LMNA
Disease	1	13.1×	0.076	LMNA

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA double-strand break attachment to nuclear envelope	1	5617.3×	0.002	LMNA
establishment or maintenance of microtubule cytoskeleton polarity	1	4213.0×	0.002	LMNA
nuclear pore localization	1	3370.4×	0.002	LMNA
negative regulation of mesenchymal cell proliferation	1	2808.7×	0.002	LMNA
protein localization to nuclear envelope	1	2106.5×	0.002	LMNA
regulation of protein localization to nucleus	1	2106.5×	0.002	LMNA
negative regulation of cardiac muscle hypertrophy in response to stress	1	1872.4×	0.002	LMNA
ventricular cardiac muscle cell development	1	1532.0×	0.002	LMNA
nuclear envelope organization	1	991.3×	0.003	LMNA
regulation of telomere maintenance	1	842.6×	0.003	LMNA
negative regulation of release of cytochrome c from mitochondria	1	802.5×	0.003	LMNA
nuclear migration	1	732.7×	0.003	LMNA
double-strand break repair via nonhomologous end joining	1	421.3×	0.004	LMNA
negative regulation of extrinsic apoptotic signaling pathway	1	421.3×	0.004	LMNA
protein localization to nucleus	1	351.1×	0.005	LMNA
cellular senescence	1	295.6×	0.005	LMNA
heterochromatin formation	1	255.3×	0.006	LMNA
muscle organ development	1	166.8×	0.008	LMNA
regulation of cell migration	1	157.5×	0.008	LMNA
protein import into nucleus	1	144.0×	0.009	LMNA
regulation of protein stability	1	125.8×	0.009	LMNA
cellular response to hypoxia	1	121.2×	0.009	LMNA
intracellular protein localization	1	104.7×	0.010	LMNA
negative regulation of cell population proliferation	1	42.1×	0.025	LMNA
positive regulation of gene expression	1	38.7×	0.026	LMNA

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
LMNA	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
LMNA	12	Binding:9, Functional:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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)
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LMNA
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.