TMEM70

Chr 8AR

transmembrane protein 70

Also known as: MC5DN2

NCBI Gene: 54968ENSG00000175606UniProt: Q9BUB7

This gene likely encodes a mitochondrial membrane protein. The encoded protein may play a role in biogenesis of mitochondrial ATP synthase. Mutations in this gene have been associated with neonatal mitochondrial encephalocardiomyopathy due to ATP synthase deficiency. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

Primary Disease Associations & Inheritance

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2MIM #614052
AR
421
ClinVar variants
67
Pathogenic / LP
0.03
pLI score
0
Active trials
Clinical Summary— TMEM70
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
67 Pathogenic / Likely Pathogenic· 177 VUS of 421 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.92LOEUF
pLI 0.029
Z-score 1.75
OE 0.40 (0.20–0.92)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.13Z-score
OE missense 0.97 (0.84–1.12)
139 obs / 143.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.40 (0.20–0.92)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.84–1.12)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.09
0≤1.21.6
LoF obs/exp: 4 / 9.9Missense obs/exp: 139 / 143.4Syn Z: -0.55

ClinVar Variant Classifications

421 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic46
Likely Pathogenic21
VUS177
Likely Benign131
Benign29
Conflicting17
46
Pathogenic
21
Likely Pathogenic
177
VUS
131
Likely Benign
29
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
14
0
32
0
46
Likely Pathogenic
15
3
3
0
21
VUS
3
131
41
2
177
Likely Benign
1
3
39
88
131
Benign
0
6
23
0
29
Conflicting
—17
Total3314313890421

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TMEM70 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TMEM70-related mitochondrial complex V (ATP synthase) deficiency, nuclear

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 2

MIM #614052

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — TMEM70
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Nuclear genetic defects of mitochondrial ATP synthase.
Hejzlarová K et al.·Physiol Res
2014Review
Variability of Clinical Phenotypes Caused by Isolated Defects of Mitochondrial ATP Synthase.
Tauchmannová K et al.·Physiol Res
2024
Novel phenotype of aortic root dilatation and late-onset metabolic decompensation in a patient with TMEM70 deficiency.
Mackay L et al.·Am J Med Genet A
2023Case report
Persistent pulmonary arterial hypertension in the newborn (PPHN): a frequent manifestation of TMEM70 defective patients.
Catteruccia M et al.·Mol Genet Metab
2014Cohort
Dual LQT1 and HCM phenotypes associated with tetrad heterozygous mutations in KCNQ1, MYH7, MYLK2, and TMEM70 genes in a three-generation Chinese family.
Wang L et al.·Europace
2016
A novel homozygous TMEM70 mutation results in congenital cataract and neonatal mitochondrial encephalo-cardiomyopathy.
Atay Z et al.·Gene
2013Case report
Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation.
Honzík T et al.·Arch Dis Child
2010
TMEM70: a mutational hot spot in nuclear ATP synthase deficiency with a pivotal role in complex V biogenesis.
Torraco A et al.·Neurogenetics
2012Case report
Investigation of myocardial dysfunction using three-dimensional speckle tracking echocardiography in a genetic positive hypertrophic cardiomyopathy Chinese family.
Wang J et al.·Cardiol Young
2018
ATP synthase deficiency due to TMEM70 mutation leads to ultrastructural mitochondrial degeneration and is amenable to treatment.
Braczynski AK et al.·Biomed Res Int
2015Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools