GFM2

Chr 5AR

GTP dependent ribosome recycling factor mitochondrial 2

Also known as: EF-G2mt, EFG2, MRRF2, MST027, MSTP027, RRF, RRF2, RRF2mt

NCBI Gene: 84340 ENSG00000164347 UniProt: Q969S9 OMIM: 606544

This gene encodes a mitochondrial translation elongation factor that functions as a GTPase to mediate ribosome disassembly from mRNA during termination of mitochondrial protein synthesis. Biallelic mutations cause combined oxidative phosphorylation deficiency 39, inherited in an autosomal recessive pattern. The pathogenic mechanism involves impaired mitochondrial translation leading to respiratory chain dysfunction and defective maintenance of mitochondrial DNA.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Eukaryotes contain two protein translational systems, one in the cytoplasm and one in the mitochondria. Mitochondrial translation is crucial for maintaining mitochondrial function and mutations in this system lead to a breakdown in the respiratory chain-oxidative phosphorylation system and to impaired maintenance of mitochondrial DNA. This gene encodes one of the mitochondrial translation elongation factors, which is a GTPase that plays a role at the termination of mitochondrial translation by mediating the disassembly of ribosomes from messenger RNA . Its role in the regulation of normal mitochondrial function and in disease states attributed to mitochondrial dysfunction is not known. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 1.041 OMIM phenotype

Clinical Summary— GFM2

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

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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

17 unique Pathogenic / Likely Pathogenic· 220 VUS of 455 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GFM2

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?

1.04LOEUF

pLI 0.000

Z-score 1.35

OE 0.78 (0.59–1.04)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.80Z-score

OE missense 0.89 (0.81–0.97)

363 obs / 408.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.78 (0.59–1.04)

0≤0.351.4

Missense OE?0.89 (0.81–0.97)

0≤0.61.4

Synonymous OE?0.81

0≤1.21.6

LoF obs/exp: 33 / 42.5Missense obs/exp: 363 / 408.3Syn Z: 1.77

This gene — mechanism propensity

0.6357th %ile

GOF

0.5367th %ile

LOF

0.3940th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

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.

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

ClinVar Variant Classifications

455 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic12

VUS220

Likely Benign134

Benign48

Conflicting15

Pathogenic

Likely Pathogenic

220

VUS

134

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	1	2	0	5
Likely Pathogenic	10	1	1	0	12
VUS	17	188	15	0	220
Likely Benign	0	16	74	44	134
Benign	0	8	38	2	48
Conflicting	—				15
Total	29	214	130	46	434

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap GFM2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →