Combined oxidative phosphorylation deficiency 55

Summary

Combined oxidative phosphorylation deficiency 55 (MONDO:0859228) is a disease caused by POLRMT (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: POLRMT (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 61

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	combined oxidative phosphorylation deficiency 55
Mondo ID	MONDO:0859228
OMIM	619743
DOID	DOID:0070428
UMLS	C5676915
MedGen	1806598
GARD	0026672
Is cancer (heuristic)	no

Data availability: 61 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › combined oxidative phosphorylation deficiency › combined oxidative phosphorylation deficiency 55

Related subtypes (57): severe X-linked mitochondrial encephalomyopathy, hepatoencephalopathy due to combined oxidative phosphorylation defect type 1, combined oxidative phosphorylation defect type 2, fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3, combined oxidative phosphorylation defect type 4, hypotonia with lactic acidemia and hyperammonemia, combined oxidative phosphorylation defect type 7, combined oxidative phosphorylation defect type 8, combined oxidative phosphorylation defect type 9, mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, combined oxidative phosphorylation defect type 11, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, combined oxidative phosphorylation defect type 13, combined oxidative phosphorylation defect type 14, combined oxidative phosphorylation defect type 15, infantile hypertrophic cardiomyopathy due to MRPL44 deficiency, combined oxidative phosphorylation defect type 17, growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome, combined oxidative phosphorylation deficiency 19, combined oxidative phosphorylation defect type 20, combined oxidative phosphorylation defect type 21, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation defect type 23, combined oxidative phosphorylation defect type 24, combined oxidative phosphorylation defect type 25, combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation defect type 27, combined oxidative phosphorylation deficiency 28, combined oxidative phosphorylation deficiency 29, combined oxidative phosphorylation defect type 30, lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome, combined oxidative phosphorylation deficiency 40, combined oxidative phosphorylation deficiency 41, combined oxidative phosphorylation deficiency 42, combined oxidative phosphorylation deficiency 43, combined oxidative phosphorylation deficiency 44, combined oxidative phosphorylation deficiency 52, combined oxidative phosphorylation deficiency 53, combined oxidative phosphorylation deficiency 54, combined oxidative phosphorylation deficiency 37, combined oxidative phosphorylation deficiency 38, combined oxidative phosphorylation deficiency 39, combined oxidative phosphorylation deficiency 45, combined oxidative phosphorylation deficiency 46, combined oxidative phosphorylation deficiency 47, combined oxidative phosphorylation deficiency 48, combined oxidative phosphorylation deficiency 51, combined oxidative phosphorylation deficiency 32, combined oxidative phosphorylation deficiency 33, combined oxidative phosphorylation deficiency 34, combined oxidative phosphorylation deficiency 35, combined oxidative phosphorylation deficiency 36, combined oxidative phosphorylation deficiency 56, combined oxidative phosphorylation deficiency 57, combined oxidative phosphorylation deficiency 58, combined oxidative phosphorylation deficiency 59, combined oxidative phosphorylation deficiency 60

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

61 retrieved; paginated sample, class counts are floors:

35 uncertain significance, 10 pathogenic, 7 likely pathogenic, 6 conflicting classifications of pathogenicity, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1341469	NM_005035.4(POLRMT):c.[1696C>T;3578C>T]		Pathogenic	no assertion criteria provided
1341477	NM_005035.4(POLRMT):c.2428C>T (p.Pro810Ser)	HCN2	Pathogenic	criteria provided, single submitter
1341473	NM_005035.4(POLRMT):c.2641-1G>C	POLRMT	Pathogenic	no assertion criteria provided
1341474	NM_005035.4(POLRMT):c.1832C>T (p.Ser611Phe)	POLRMT	Pathogenic	no assertion criteria provided
1341475	NM_005035.4(POLRMT):c.1923C>G (p.Phe641Leu)	POLRMT	Pathogenic	no assertion criteria provided
1341476	NM_005035.4(POLRMT):c.2775C>A (p.Cys925Ter)	POLRMT	Pathogenic	criteria provided, multiple submitters, no conflicts
1341478	NM_005035.4(POLRMT):c.3037C>T (p.Arg1013Cys)	POLRMT	Pathogenic	no assertion criteria provided
1341479	NM_005035.4(POLRMT):c.445C>T (p.Gln149Ter)	POLRMT	Pathogenic	no assertion criteria provided
4528323	NM_005035.4(POLRMT):c.1940C>T (p.Pro647Leu)	POLRMT	Pathogenic	no assertion criteria provided
4528326	NM_005035.4(POLRMT):c.2438T>C (p.Phe813Ser)	POLRMT	Pathogenic	no assertion criteria provided
1341472	NM_005035.4(POLRMT):c.748C>G (p.His250Asp)	POLRMT	Likely pathogenic	criteria provided, single submitter
2671936	NM_005035.4(POLRMT):c.954-1G>C	POLRMT	Likely pathogenic	criteria provided, single submitter
3237469	NM_005035.4(POLRMT):c.2041C>T (p.Gln681Ter)	POLRMT	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3367088	NM_005035.4(POLRMT):c.1753C>T (p.Gln585Ter)	POLRMT	Likely pathogenic	criteria provided, single submitter
4277451	NM_005035.4(POLRMT):c.2732_2733delinsT (p.Ala911fs)	POLRMT	Likely pathogenic	criteria provided, single submitter
4796499	NM_005035.4(POLRMT):c.2351C>T (p.Ser784Leu)	POLRMT	Likely pathogenic	criteria provided, single submitter
4814169	NM_005035.4(POLRMT):c.983dup (p.Lys329fs)	POLRMT	Likely pathogenic	criteria provided, single submitter
1341471	NM_005035.4(POLRMT):c.2225_2242del (p.Pro742_Pro747del)	POLRMT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1676658	NM_005035.4(POLRMT):c.3459C>G (p.Tyr1153Ter)	POLRMT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2441735	NM_005035.4(POLRMT):c.2029G>A (p.Ala677Thr)	POLRMT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2582453	NM_005035.4(POLRMT):c.232G>A (p.Val78Met)	POLRMT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2582470	NM_005035.4(POLRMT):c.757C>T (p.Arg253Trp)	POLRMT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2689808	NM_005035.4(POLRMT):c.578G>A (p.Arg193Gln)	POLRMT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1341470	NM_005035.4(POLRMT):c.2608G>A (p.Asp870Asn)	POLRMT	Uncertain significance	criteria provided, single submitter
1679186	NM_005035.4(POLRMT):c.881C>T (p.Pro294Leu)	POLRMT	Uncertain significance	criteria provided, single submitter
1679187	NM_005035.4(POLRMT):c.1855G>A (p.Gly619Ser)	POLRMT	Uncertain significance	criteria provided, single submitter
2207731	NM_005035.4(POLRMT):c.789G>T (p.Met263Ile)	POLRMT	Uncertain significance	criteria provided, multiple submitters, no conflicts
2349432	NM_005035.4(POLRMT):c.1340G>A (p.Arg447Gln)	POLRMT	Uncertain significance	criteria provided, multiple submitters, no conflicts
2407957	NM_005035.4(POLRMT):c.1226C>T (p.Ala409Val)	POLRMT	Uncertain significance	criteria provided, multiple submitters, no conflicts
2442139	NM_005035.4(POLRMT):c.1378G>C (p.Val460Leu)	POLRMT	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 0 · 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
POLRMT	Strong	Autosomal recessive	combined oxidative phosphorylation deficiency 55	6

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
POLRMT	HGNC:9200	ENSG00000099821	O00411	DNA-directed RNA polymerase, mitochondrial	gencc,clinvar
HCN2	HGNC:4846	ENSG00000099822	Q9UL51	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLRMT	DNA-directed RNA polymerase, mitochondrial	DNA-dependent RNA polymerase catalyzes the transcription of mitochondrial DNA into RNA using the four ribonucleoside triphosphates as substrates.
HCN2	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2	Hyperpolarization-activated ion channel that is permeable to sodium and potassium ions.

Protein-family classification

Druggable: 2 · 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
Ion channel	1	55.8×	0.036
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLRMT	Enzyme (other)	yes	2.7.7.6	DNA-dir_Rpol_phage-type, TPR-like_helical_dom_sf, RPOL_N
HCN2	Ion channel	yes		cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
left testis	1
right testis	1
C1 segment of cervical spinal cord	1
putamen	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLRMT	251	ubiquitous	marker	left testis, right testis, apex of heart
HCN2	177	broad	yes	C1 segment of cervical spinal cord, right frontal lobe, putamen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLRMT	2,630
HCN2	1,103

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLRMT	O00411	25
HCN2	Q9UL51	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Mitochondrial transcription initiation	1	1903.3×	0.002	POLRMT
HCN channels	1	1427.5×	0.002	HCN2
Transcription from mitochondrial promoters	1	1427.5×	0.002	POLRMT
Strand-asynchronous mitochondrial DNA replication	1	571.0×	0.004	POLRMT
DNA Replication	1	119.0×	0.015	POLRMT
Transcriptional activation of mitochondrial biogenesis	1	102.0×	0.015	POLRMT
Mitochondrial biogenesis	1	84.0×	0.015	POLRMT
Organelle biogenesis and maintenance	1	33.0×	0.034	POLRMT
Gene expression (Transcription)	1	8.9×	0.109	POLRMT

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
transcription initiation at mitochondrial promoter	1	2106.5×	0.003	POLRMT
mitochondrial transcription	1	1203.7×	0.003	POLRMT
cellular response to aldosterone	1	1203.7×	0.003	HCN2
cellular response to cGMP	1	1053.2×	0.003	HCN2
regulation of membrane depolarization	1	936.2×	0.003	HCN2
ammonium transmembrane transport	1	936.2×	0.003	HCN2
mitochondrial DNA replication	1	766.0×	0.003	POLRMT
membrane depolarization during cardiac muscle cell action potential	1	702.2×	0.003	HCN2
sodium ion import across plasma membrane	1	312.1×	0.006	HCN2
potassium ion import across plasma membrane	1	183.2×	0.009	HCN2
cellular response to cAMP	1	145.3×	0.010	HCN2
regulation of membrane potential	1	115.4×	0.012	HCN2
sodium ion transmembrane transport	1	101.5×	0.012	HCN2
potassium ion transmembrane transport	1	68.0×	0.017	HCN2
cell-cell signaling	1	34.8×	0.029	HCN2
response to xenobiotic stimulus	1	34.5×	0.029	HCN2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
POLRMT	0	0
HCN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
POLRMT	20	Binding:12, ADMET:7, Functional:1
HCN2	12	Binding:6, Functional:4, ADMET:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POLRMT	2.7.7.6	DNA-directed RNA polymerase

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

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	2	POLRMT, HCN2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
POLRMT	20	—
HCN2	12	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.