Cerebrooculofacioskeletal syndrome 3

Summary

Cerebrooculofacioskeletal syndrome 3 (MONDO:0014696) is a disease caused by ERCC5 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ERCC5 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 72

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebrooculofacioskeletal syndrome 3
Mondo ID	MONDO:0014696
MeSH	C565035
OMIM	616570
DOID	DOID:0080913
UMLS	C1851443
MedGen	342008
GARD	0016140
Is cancer (heuristic)	no

Also known as: cerebrooculofacioskeletal syndrome 3 · cerebrooculofacioskeletal syndrome type 3 · COFS3

Data availability: 72 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 › autosomal genetic disease › autosomal recessive disease › COFS syndrome › cerebrooculofacioskeletal syndrome 3

Related subtypes (4): cerebrooculofacioskeletal syndrome 1, xeroderma pigmentosum group G, cerebrooculofacioskeletal syndrome 2, cerebrooculofacioskeletal syndrome 4

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

72 retrieved; paginated sample, class counts are floors:

29 uncertain significance, 14 likely pathogenic, 10 conflicting classifications of pathogenicity, 8 pathogenic, 6 pathogenic/likely pathogenic, 3 benign/likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028077	NM_000123.4(ERCC5):c.1855C>T (p.Gln619Ter)	BIVM-ERCC5	Pathogenic	criteria provided, single submitter
1049176	NM_000123.4(ERCC5):c.1096C>T (p.Arg366Ter)	BIVM-ERCC5	Pathogenic	criteria provided, multiple submitters, no conflicts
1335951	NM_000123.4(ERCC5):c.673-2A>G	BIVM-ERCC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16568	NM_000123.4(ERCC5):c.2775del (p.Gly926fs)	BIVM-ERCC5	Pathogenic	no assertion criteria provided
16574	NM_000123.4(ERCC5):c.1115_1118del (p.Arg372fs)	BIVM-ERCC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16576	NM_000123.4(ERCC5):c.2751del (p.Lys917fs)	BIVM-ERCC5	Pathogenic	criteria provided, multiple submitters, no conflicts
1690897	NM_000123.4(ERCC5):c.2705dup (p.Asn902fs)	BIVM-ERCC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209978	NM_000123.4(ERCC5):c.2766dup (p.Leu923fs)	BIVM-ERCC5	Pathogenic	criteria provided, single submitter
3575647	NM_000123.4(ERCC5):c.410_411dup (p.Arg138fs)	BIVM-ERCC5	Pathogenic	criteria provided, single submitter
3575661	NM_000123.4(ERCC5):c.2836G>T (p.Gly946Ter)	BIVM-ERCC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3769228	NM_000123.4(ERCC5):c.120del (p.Gly41fs)	BIVM-ERCC5	Pathogenic	criteria provided, single submitter
4533354	NM_000123.4(ERCC5):c.2739del (p.Lys913_Val914insTer)	BIVM-ERCC5	Pathogenic	criteria provided, single submitter
517221	NM_000123.4(ERCC5):c.1173dup (p.Lys392Ter)	BIVM-ERCC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800881	NM_000123.4(ERCC5):c.2427del (p.Asp809fs)	BIVM-ERCC5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1217258	NM_000123.4(ERCC5):c.1068del (p.Ser357fs)	BIVM-ERCC5	Likely pathogenic	criteria provided, single submitter
16567	NM_000123.4(ERCC5):c.2375C>T (p.Ala792Val)	BIVM-ERCC5	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723328	NM_000123.4(ERCC5):c.2705del (p.Asn902fs)	BIVM-ERCC5	Likely pathogenic	criteria provided, single submitter
3235065	NM_000123.4(ERCC5):c.480del (p.Asp161fs)	BIVM-ERCC5	Likely pathogenic	criteria provided, single submitter
3382284	NM_000123.4(ERCC5):c.265-2A>G	BIVM-ERCC5	Likely pathogenic	criteria provided, single submitter
3575646	NM_000123.4(ERCC5):c.265-1G>T	BIVM-ERCC5	Likely pathogenic	criteria provided, single submitter
3575648	NM_000123.4(ERCC5):c.812del (p.Gly271fs)	BIVM-ERCC5	Likely pathogenic	criteria provided, single submitter
3575649	NM_000123.4(ERCC5):c.897del (p.Val300fs)	BIVM-ERCC5	Likely pathogenic	criteria provided, single submitter
3575651	NM_000123.4(ERCC5):c.1160_1183delinsA (p.Thr387fs)	BIVM-ERCC5	Likely pathogenic	criteria provided, single submitter
3575653	NM_000123.4(ERCC5):c.1463dup (p.Ser489fs)	BIVM-ERCC5	Likely pathogenic	criteria provided, single submitter
3575655	NM_000123.4(ERCC5):c.1924G>T (p.Glu642Ter)	BIVM-ERCC5	Likely pathogenic	criteria provided, single submitter
3575658	NM_000123.4(ERCC5):c.2431del (p.Ser811fs)	BIVM-ERCC5	Likely pathogenic	criteria provided, single submitter
3575660	NM_000123.4(ERCC5):c.2533G>T (p.Gly845Ter)	BIVM-ERCC5	Likely pathogenic	criteria provided, single submitter
977918	NM_000123.3:c.89-?_528+?del	ERCC5	Likely pathogenic	no assertion criteria provided
134159	NM_000123.4(ERCC5):c.56C>T (p.Pro19Leu)	BIVM-ERCC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134167	NM_000123.4(ERCC5):c.3038A>G (p.Gln1013Arg)	BIVM-ERCC5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
ERCC5	Strong	Autosomal recessive	cerebrooculofacioskeletal syndrome 3	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERCC5	Orphanet:1466	COFS syndrome
ERCC5	Orphanet:220295	Xeroderma pigmentosum-Cockayne syndrome complex
ERCC5	Orphanet:910	Xeroderma pigmentosum

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ERCC5	HGNC:3437	ENSG00000134899	P28715	DNA excision repair protein ERCC-5	gencc,clinvar
BIVM-ERCC5	HGNC:43690	ENSG00000270181		BIVM-ERCC5 readthrough	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERCC5	DNA excision repair protein ERCC-5	Single-stranded structure-specific DNA endonuclease involved in DNA excision repair.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERCC5	Other/Unknown	no		XPG/Rad2_eukaryotes, XPG/Rad2, XPG_DNA_repair_N
BIVM-ERCC5	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

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
body of pancreas	1
calcaneal tendon	1
granulocyte	1
male germ line stem cell (sensu Vertebrata) in testis	1
tonsil	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERCC5	166	ubiquitous	yes	granulocyte, calcaneal tendon, body of pancreas
BIVM-ERCC5	108	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, tonsil, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERCC5	2,749
BIVM-ERCC5	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERCC5	P28715	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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
Dual Incision in GG-NER	1	259.6×	0.006	ERCC5
Formation of Incision Complex in GG-NER	1	253.8×	0.006	ERCC5
Dual incision in TC-NER	1	173.0×	0.006	ERCC5

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
base-excision repair, AP site formation	1	3370.4×	0.002	ERCC5
response to UV-C	1	1685.2×	0.002	ERCC5
transcription-coupled nucleotide-excision repair	1	1203.7×	0.002	ERCC5
nucleotide-excision repair	1	383.0×	0.004	ERCC5
response to UV	1	366.4×	0.004	ERCC5
double-strand break repair via homologous recombination	1	156.0×	0.007	ERCC5
negative regulation of apoptotic process	1	34.8×	0.029	ERCC5

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERCC5	0	0
BIVM-ERCC5	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
ERCC5	3	Binding: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

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	ERCC5, BIVM-ERCC5

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)
ERCC5	3	—
BIVM-ERCC5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.