GFM2

protein-coding

GTP dependent ribosome recycling factor mitochondrial 2

Gene summary

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]

MANE transcript

NM_032380.5

Inheritance

ClinVar variants

P:16U:216B:77

Top phenotype

Combined oxidative phosphorylation deficiency 39

gnomAD constraint

pLI —, LoF o/e 0.78

Max pathogenic AF

—

Genomic locus

chr5:74,721,206-74,767,147

External References & Databases

Ensembl (ENSG00000164347)

Transcript & Mutation Effects

hg38 • Region Span ~45.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

combined oxidative phosphorylation deficiency 39STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032726

Submitter: PanelApp Australia

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between GFM2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 9, 2019. The GFM2 gene encodes mitochondrial elongation factor G2, which plays an important role in mitochondrial translation by recycling the mitochondrial ribosome after translation termination. The GFM2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2015 (PMID: 26016410). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five unique variants identified in three unrelated cases from two publications (PMIDs: 26016410, 29075935). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function (PMID: 19716793). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel December 9, 2019 (SOP Version 7).

combined oxidative phosphorylation deficiency 39SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032726

Submitter: Orphanet

combined oxidative phosphorylation deficiency 39LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032726

Submitter: Labcorp Genetics (formerly Invitae)

combined oxidative phosphorylation deficiency 39MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032726

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 39AR

Manifestation: Biochemical; Neurologic; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 22700954; 26016410; 29075935

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GFM2 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 306

Inborn genetic diseasesTotal: 98

not specifiedTotal: 54

Combined oxidative phosphorylation deficiency 39Total: 36

GFM2-related disorderTotal: 17

Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1Total: 3

Mitochondrial diseaseTotal: 3

Sandhoff diseaseTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032380.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				46 clinvar	1 clinvar	47
missense	1 clinvar	1 clinvar	188 clinvar	27 clinvar	3 clinvar	220
nonsense		4 clinvar	7 clinvar			11
start loss			1 clinvar			1
frameshift	1 clinvar	5 clinvar	9 clinvar			15
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	11 clinvar			15
Total	3	13	216	73	4	309

Highest pathogenic variant AF is 0.00006637709

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032380.5	RefSeq	NP_115756.2	20	MANE Select
ENST00000296805.8	Ensembl	ENSP00000296805.3	20	MANE Select
NM_001281302.2	RefSeq	NP_001268231.1	21	Standard
NM_170681.3	RefSeq	NP_733781.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Translation
Metabolism of proteins
Purine metabolism
Mitochondrial translation termination
Mitochondrial translation

Biological Process

mitochondrial translation
ribosome disassembly
mitochondrial translational elongation
mitochondrial translational termination

Molecular Function

translation elongation factor activity
GTPase activity
protein binding
GTP binding

Cellular Component

mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296805
Coding exons: 20
Length: 46168
Individuals with no LoFs: 125626
Homozygous LoFs: 0
Heterozygous LoFs: 119
Defined: 125745
p: 0.000473

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.797	363	408	0.889	0.0000203	5038
Missense (PolyPhen)		136	167.14	0.81371		2069
Synonymous	1.77	115	142	0.811	0.00000690	1509
Loss of Function	1.35	33	42.5	0.777	0.00000232	545

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.0011	0.00098	notable
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00044	0.00044	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00039	0.00039	rare
South Asian	0.00058	0.00056	rare
Other	0.0011	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mitochondrial GTPase that mediates the disassembly of ribosomes from messenger RNA at the termination of mitochondrial protein biosynthesis. Acts in collaboration with MRRF. GTP hydrolysis follows the ribosome disassembly and probably occurs on the ribosome large subunit. Not involved in the GTP-dependent ribosomal translocation step during translation elongation. {ECO:0000255|HAMAP-Rule:MF_03059, ECO:0000269|PubMed:19716793}.;

Intolerance Scores

LoFtool: 0.990
RVIS EVS: 1.16
RVIS percentile EVS: 92.59

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.875

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High