Cerebroretinal microangiopathy with calcifications and cysts 3

Summary

Cerebroretinal microangiopathy with calcifications and cysts 3 (MONDO:0957264) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 29

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebroretinal microangiopathy with calcifications and cysts 3
Mondo ID	MONDO:0957264
OMIM	620368
UMLS	C5830497
MedGen	1841133
GARD	0026803
Is cancer (heuristic)	no

Data availability: 29 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › congenital vitreoretinal dysplasia › Coats plus syndrome › cerebroretinal microangiopathy with calcifications and cysts 3

Related subtypes (2): cerebroretinal microangiopathy with calcifications and cysts 2, cerebroretinal microangiopathy with calcifications and cysts 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

29 retrieved; paginated sample, class counts are floors:

11 conflicting classifications of pathogenicity, 9 uncertain significance, 2 likely benign, 2 pathogenic/likely pathogenic, 2 benign/likely benign, 2 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
475014	NM_015450.3(POT1):c.10-2A>C	POT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
475019	NM_015450.3(POT1):c.1087C>T (p.Arg363Ter)	POT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3594292	NM_015450.3(POT1):c.991_1006+7del	POT1	Likely pathogenic	criteria provided, single submitter
1418306	NM_015450.3(POT1):c.1369+5G>A	POT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436392	NM_015450.3(POT1):c.64A>G (p.Ile22Val)	POT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475027	NM_015450.3(POT1):c.1178A>G (p.His393Arg)	POT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475066	NM_015450.3(POT1):c.1841A>G (p.Asn614Ser)	POT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475112	NM_015450.3(POT1):c.903G>T (p.Gln301His)	POT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475115	NM_015450.3(POT1):c.977T>C (p.Val326Ala)	POT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
486129	NM_015450.3(POT1):c.1186G>A (p.Asp396Asn)	POT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
486133	NM_015450.3(POT1):c.1814G>C (p.Cys605Ser)	POT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
541891	NM_015450.3(POT1):c.1707A>C (p.Pro569=)	POT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
571862	NM_015450.3(POT1):c.1505+3A>G	POT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
819368	NM_015450.3(POT1):c.1490C>A (p.Thr497Lys)	POT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1356860	NM_015450.3(POT1):c.1219A>G (p.Lys407Glu)	POT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1405674	NM_015450.3(POT1):c.1634C>T (p.Thr545Ile)	POT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1504733	NM_015450.3(POT1):c.965C>T (p.Ser322Leu)	POT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
475030	NM_015450.3(POT1):c.1213G>A (p.Ala405Thr)	POT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
475039	NM_015450.3(POT1):c.1363A>G (p.Ile455Val)	POT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
475044	NM_015450.3(POT1):c.1416T>G (p.Ser472Arg)	POT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
574011	NM_015450.3(POT1):c.1106A>G (p.Tyr369Cys)	POT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
818753	NM_015450.3(POT1):c.1270T>C (p.Trp424Arg)	POT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
822128	NM_015450.3(POT1):c.1082G>A (p.Arg361His)	POT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1597127	NM_015450.3(POT1):c.1434T>C (p.Ser478=)	POT1	Likely benign	criteria provided, multiple submitters, no conflicts
475037	NM_015450.3(POT1):c.1338G>A (p.Pro446=)	POT1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
475068	NM_015450.3(POT1):c.1884A>C (p.Thr628=)	POT1	Benign	criteria provided, multiple submitters, no conflicts
475104	NM_015450.3(POT1):c.813C>T (p.Tyr271=)	POT1	Likely benign	criteria provided, multiple submitters, no conflicts
475114	NM_015450.3(POT1):c.924A>G (p.Gln308=)	POT1	Benign	criteria provided, multiple submitters, no conflicts
823207	NM_015450.3(POT1):c.939C>T (p.Asp313=)	POT1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
POT1	Limited	Autosomal recessive	cerebroretinal microangiopathy with calcifications and cysts 3	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POT1	Orphanet:251627	Oligodendroglioma
POT1	Orphanet:251630	Anaplastic oligodendroglioma
POT1	Orphanet:618	Familial melanoma
POT1	Orphanet:67038	B-cell chronic lymphocytic leukemia

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
POT1	HGNC:17284	ENSG00000128513	Q9NUX5	Protection of telomeres protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POT1	Protection of telomeres protein 1	Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini.

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)
POT1	Other/Unknown	no		Telomer_end-bd_POT1/Cdc13, NA-bd_OB-fold, POT1

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
calcaneal tendon	1
germinal epithelium of ovary	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POT1	279	ubiquitous	marker	secondary oocyte, germinal epithelium of ovary, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POT1	1,842

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POT1	Q9NUX5	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. 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
Telomere C-strand synthesis initiation	1	815.7×	0.006	POT1
Processive synthesis on the C-strand of the telomere	1	761.3×	0.006	POT1
Telomere C-strand (Lagging Strand) Synthesis	1	761.3×	0.006	POT1
Removal of the Flap Intermediate from the C-strand	1	634.4×	0.006	POT1
Telomere Extension By Telomerase	1	456.8×	0.006	POT1
Polymerase switching on the C-strand of the telomere	1	423.0×	0.006	POT1
Packaging Of Telomere Ends	1	219.6×	0.007	POT1
Recognition and association of DNA glycosylase with site containing an affected purine	1	203.9×	0.007	POT1
Cleavage of the damaged purine	1	203.9×	0.007	POT1
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	184.2×	0.007	POT1
Cleavage of the damaged pyrimidine	1	184.2×	0.007	POT1
Inhibition of DNA recombination at telomere	1	167.9×	0.007	POT1
DNA Damage/Telomere Stress Induced Senescence	1	163.1×	0.007	POT1
Meiotic synapsis	1	141.0×	0.007	POT1

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
positive regulation of DNA strand elongation	1	16852.0×	4e-04	POT1
positive regulation of telomeric D-loop disassembly	1	16852.0×	4e-04	POT1
telomere assembly	1	4213.0×	9e-04	POT1
regulation of double-strand break repair via nonhomologous end joining	1	3370.4×	9e-04	POT1
regulation of telomere maintenance via telomerase	1	2808.7×	9e-04	POT1
establishment of protein localization to telomere	1	2106.5×	9e-04	POT1
telomeric D-loop disassembly	1	1872.4×	9e-04	POT1
telomere capping	1	1296.3×	0.001	POT1
telomere maintenance via telomerase	1	732.7×	0.001	POT1
negative regulation of telomere maintenance via telomerase	1	732.7×	0.001	POT1
positive regulation of telomere maintenance via telomerase	1	732.7×	0.001	POT1
positive regulation of telomere maintenance	1	510.7×	0.002	POT1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POT1	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
POT1	1	Binding:1

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	1	POT1

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)
POT1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.