CHCHD10

Chr 22AD

coiled-coil-helix-coiled-coil-helix domain containing 10

Also known as: C22orf16, FTDALS2, IMMD, MIX17A, N27C7-4, SMAJ

NCBI Gene: 400916 ENSG00000250479 UniProt: Q8WYQ3 OMIM: 615903

The protein is enriched at mitochondrial cristae junctions in the intermembrane space and maintains mitochondrial organization and cristae structure. Autosomal dominant mutations cause frontotemporal dementia and/or amyotrophic lateral sclerosis-2, isolated mitochondrial myopathy, and Jokela-type spinal muscular atrophy. The pathogenic mechanism appears to be dominant-negative, where mutant proteins interfere with normal mitochondrial function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a mitochondrial protein that is enriched at cristae junctions in the intermembrane space. It may play a role in cristae morphology maintenance or oxidative phosphorylation. Mutations in this gene cause frontotemporal dementia and/or amyotrophic lateral sclerosis-2. Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 7 and 19. [provided by RefSeq, Aug 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.913 OMIM phenotypes

Clinical Summary— CHCHD10

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 148 VUS of 287 total submissions

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Clinical Trials

5 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CHCHD10

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.91LOEUF

pLI 0.000

Z-score -0.75

OE 1.35 (0.73–1.91)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.82Z-score

OE missense 0.71 (0.56–0.91)

47 obs / 65.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.35 (0.73–1.91)

0≤0.351.4

Missense OE?0.71 (0.56–0.91)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 7 / 5.2Missense obs/exp: 47 / 65.8Syn Z: -0.41

This gene — mechanism propensity

0.7230th %ile

GOF

0.5759th %ile

LOF

0.2777th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOF1 literature citation

LOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNIn this study, we made a series of observations utilizing Caenorhabditis elegans models, mammalian cell lines, primary neurons and mouse brains, demonstrating that CHCHD10 normally exerts a protective role in mitochondrial and synaptic integrity as well as in the retention of nuclear TDP-43, whereas1

GOFThese aggregates may be related to the CHCHD10 aggregates recently described to cause mitochondrial degeneration and disease in a tissue-selective toxic gain-of-function fashion in a CHCHD10 knock-in mouse model.2

LOFThus, our data show that the CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

ClinVar Variant Classifications

287 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic2

VUS148

Likely Benign105

Benign16

Conflicting11

Pathogenic

Likely Pathogenic

148

VUS

105

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	0	2	0	0	2
VUS	15	111	18	4	148
Likely Benign	0	13	39	53	105
Benign	0	2	12	2	16
Conflicting	—				11
Total	15	132	69	59	286

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

View in ClinVar →

59 pathogenic / likely-pathogenic (of 114) ClinVar copy-number / structural variants overlap CHCHD10 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →