Meier-Gorlin syndrome 3

Summary

Meier-Gorlin syndrome 3 (MONDO:0013430) is a disease caused by ORC6 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ORC6 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 45

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Meier-Gorlin syndrome 3
Mondo ID	MONDO:0013430
OMIM	613803
DOID	DOID:0080514
UMLS	C3151113
MedGen	462463
GARD	0015710
Is cancer (heuristic)	no

Also known as: Meier-Gorlin syndrome 3 · Meier-Gorlin syndrome caused by mutation in ORC6 · Meier-Gorlin syndrome type 3 · MGORS3 · ORC6 Meier-Gorlin syndrome

Data availability: 45 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Meier-Gorlin syndrome › Meier-Gorlin syndrome 3

Related subtypes (9): Meier-Gorlin syndrome 1, Meier-Gorlin syndrome 2, Meier-Gorlin syndrome 4, Meier-Gorlin syndrome 5, Meier-Gorlin syndrome 6, Meier-Gorlin syndrome 7, Meier-Gorlin syndrome 8, Meier-Gorlin syndrome 9, Meier-Gorlin syndrome 10

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

45 retrieved; paginated sample, class counts are floors:

25 uncertain significance, 7 conflicting classifications of pathogenicity, 6 pathogenic, 4 benign, 1 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1173059	NM_014321.4(ORC6):c.71C>T (p.Ala24Val)	ORC6	Pathogenic	criteria provided, single submitter
1173060	NM_014321.4(ORC6):c.65G>A (p.Arg22Lys)	ORC6	Pathogenic	criteria provided, single submitter
253274	NM_014321.4(ORC6):c.602_605del (p.Lys201fs)	ORC6	Pathogenic	no assertion criteria provided
2967020	NM_014321.4(ORC6):c.507dup (p.Ala170fs)	ORC6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30655	NM_014321.4(ORC6):c.257_258del (p.Ser85_Phe86insTer)	ORC6	Pathogenic	criteria provided, multiple submitters, no conflicts
30656	NM_014321.4(ORC6):c.695A>C (p.Tyr232Ser)	ORC6	Pathogenic	criteria provided, single submitter
436124	NM_014321.4(ORC6):c.1A>G (p.Met1Val)	ORC6	Pathogenic	criteria provided, single submitter
977909	NM_014321.4(ORC6):c.360-1G>T	ORC6	Likely pathogenic	no assertion criteria provided
211808	NM_014321.4(ORC6):c.360-13A>G	ORC6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
253272	NM_014321.4(ORC6):c.2T>C (p.Met1Thr)	ORC6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
253273	NM_014321.4(ORC6):c.449+5G>A	ORC6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
319301	NM_014321.4(ORC6):c.96G>C (p.Arg32=)	ORC6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436123	NM_014321.4(ORC6):c.235T>A (p.Tyr79Asn)	ORC6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884771	NM_014321.4(ORC6):c.552G>A (p.Gln184=)	ORC6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
887920	NM_014321.4(ORC6):c.27A>G (p.Leu9=)	ORC6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129865	NM_014321.4(ORC6):c.207T>G (p.Ile69Met)	ORC6	Uncertain significance	criteria provided, multiple submitters, no conflicts
319300	NM_014321.4(ORC6):c.23G>T (p.Arg8Leu)	ORC6	Uncertain significance	criteria provided, multiple submitters, no conflicts
319302	NM_014321.4(ORC6):c.413C>A (p.Pro138Gln)	ORC6	Uncertain significance	criteria provided, multiple submitters, no conflicts
319303	NM_014321.4(ORC6):c.450-4G>A	ORC6	Uncertain significance	criteria provided, single submitter
319304	NM_014321.4(ORC6):c.556G>T (p.Val186Phe)	ORC6	Uncertain significance	criteria provided, multiple submitters, no conflicts
319305	NM_014321.4(ORC6):c.*115T>G	ORC6	Uncertain significance	criteria provided, single submitter
319307	NM_014321.4(ORC6):c.*232A>T	ORC6	Uncertain significance	criteria provided, single submitter
319308	NM_014321.4(ORC6):c.*307A>G	ORC6	Uncertain significance	criteria provided, single submitter
319309	NM_014321.4(ORC6):c.*363C>T	ORC6	Uncertain significance	criteria provided, single submitter
319314	NM_014321.4(ORC6):c.*582A>C	ORC6	Uncertain significance	criteria provided, single submitter
319315	NM_014321.4(ORC6):c.*594A>G	ORC6	Uncertain significance	criteria provided, single submitter
319318	NM_014321.4(ORC6):c.*598G>A	ORC6	Uncertain significance	criteria provided, single submitter
319323	NM_014321.4(ORC6):c.*621T>C	ORC6	Uncertain significance	criteria provided, single submitter
319324	NM_014321.4(ORC6):c.*640G>A	ORC6	Uncertain significance	criteria provided, single submitter
884770	NM_014321.4(ORC6):c.430G>A (p.Ala144Thr)	ORC6	Uncertain significance	criteria provided, single submitter

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
ORC6	Definitive	Autosomal recessive	Meier-Gorlin syndrome 3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ORC6	Orphanet:2554	Ear-patella-short stature syndrome

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
ORC6	HGNC:17151	ENSG00000091651	Q9Y5N6	Origin recognition complex subunit 6	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ORC6	Origin recognition complex subunit 6	Component of the origin recognition complex (ORC) that binds origins of replication.

Protein-family classification

Druggable: 1 · 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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ORC6	Enzyme (other)	yes	3.6.4.B8	ORC6_cyclin_first, ORC6_met/pln, ORC6_cyclin-like_2nd

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
endothelial cell	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ORC6	249	ubiquitous	marker	oocyte, endothelial cell, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ORC6	1,321

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ORC6	Q9Y5N6	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
CDC6 association with the ORC:origin complex	1	1427.5×	0.003	ORC6
E2F-enabled inhibition of pre-replication complex formation	1	1268.9×	0.003	ORC6
Activation of the pre-replicative complex	1	326.3×	0.006	ORC6
Activation of ATR in response to replication stress	1	300.5×	0.006	ORC6
Orc1 removal from chromatin	1	178.4×	0.007	ORC6
Assembly of the ORC complex at the origin of replication	1	165.5×	0.007	ORC6
Assembly of the pre-replicative complex	1	139.3×	0.007	ORC6

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 replication initiation	1	624.1×	0.002	ORC6

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ORC6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ORC6	3.6.4.B8

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	1	ORC6
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)
ORC6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.