MGME1

protein-coding

mitochondrial genome maintenance exonuclease 1, the group of Exonucleases

Gene summary

The protein encoded by this gene is a nuclear-encoded mitochondrial protein necessary for the maintenance of mitochondrial genome synthesis. The encoded protein is a RecB-type exonuclease and primarily cleaves single-stranded DNA. Defects in this gene have been associated with mitochondrial DNA depletion syndrome-11. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

Previous symbols:

C20orf72

MANE transcript

NM_052865.4

Inheritance

ClinVar variants

P:13U:98B:50

Top phenotype

Mitochondrial DNA depletion syndrome 11

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr20:17,969,018-17,991,122

External References & Databases

Ensembl (ENSG00000125871)

Transcript & Mutation Effects

hg38 • Region Span ~22.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MGME1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 7, 2023. The *MGME1* gene encodes metal-dependent single-stranded DNA (ssDNA) exonuclease which is involved in mitochondrial genome DNA replication termination and is essential for maintenance and stability of the mitochondrial DNA (mtDNA). The *MGME1* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2013 (PMID: 23313956), in three individuals with ophthalmoplegia, myopathy, and respiratory failure. While various names could be given to the constellation of features seen in those with *MGME1*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MGME1* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four unique variants reported in five probands from three publications (PMIDs: 23313956, 28711739, 37429773). Variants included one frameshift, two nonsense, and one missense. The c.456G>A (p.Trp152Ter) variant was identified in two families from Lebanon and Italy that shared a common haplotype and is a proposed founder variant (PMID: 23313956). In the few affected individuals reported to date, the disorder is characterized by progressive external ophthalmoplegia and neuromuscular symptoms including muscle wasting, proximal weakness, exercise intolerance, and respiratory distress. Other features may include profound emaciation, spinal deformities, gastrointestinal issues and cardiac phenotypes such as arrythmias and dilated cardiomyopathy. Brain MRI findings include cerebellar atrophy. As well as phenotypic heterogeneity, a range in age of onset is observed, ranging from infant onset to the fourth decade. At least three additional cases are reported in the medical literature (PMIDs: 25058219, 28097321, 32528171) but were not included in this curation given limited clinical details provided. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease. Abnormal replication of the mitochondrial genome has been demonstrated in patient fibroblasts and a *Mgme1* knockout mouse model which also recapitulates aspects of primary mitochondrial disease (PMIDs: 23313956, 29572490, 35533204). In summary, there is definitive evidence to support the relationship between *MGME1* and primary mitochondrial disease. This relationship has been demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 7, 2023 (SOP Version 9).

mitochondrial DNA depletion syndrome 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014039

Submitter: PanelApp Australia

mitochondrial DNA depletion syndrome 11SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014039

Submitter: Orphanet

mitochondrial DNA depletion syndrome 11STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014039

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial DNA depletion syndrome 11AR

Manifestation: Biochemical; Cardiovascular; Endocrine; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: In addition to other manifestations, the condition has been described as including cardiovascular sequelae (eg, dilated cardiomyopathy, arrhythymias), and awareness may allow appropriate surveillance and prompt management

Refs: 23313956

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MGME1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 146

Inborn genetic diseasesTotal: 53

Mitochondrial DNA depletion syndrome 11Total: 15

MGME1-related disorderTotal: 12

not specifiedTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_052865.4. 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				38 clinvar		38
missense			94 clinvar	11 clinvar	1 clinvar	106
nonsense	4 clinvar	2 clinvar				6
start loss			1 clinvar			1
frameshift	5 clinvar	2 clinvar	3 clinvar			10
splice donor/acceptor (+/-2bp)						0
Total	9	4	98	49	1	161

Highest pathogenic variant AF is 0.000006815433

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 75 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_052865.4	RefSeq	NP_443097.1	4	MANE Select
ENST00000377710.10	Ensembl	ENSP00000366939.5	4	MANE Select
NM_001310338.2	RefSeq	NP_001297267.1	5	Standard
NM_001310339.2	RefSeq	NP_001297268.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mitochondrial genome maintenance
mitochondrial DNA replication
mitochondrial DNA repair
nucleic acid phosphodiester bond hydrolysis

Molecular Function

single-stranded DNA exodeoxyribonuclease activity

Cellular Component

mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377710
Coding exons: 4
Length: 22210
Individuals with no LoFs: 125717
Homozygous LoFs: 0
Heterozygous LoFs: 31
Defined: 125748
p: 0.000123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.258	187	177	1.05	0.00000812	2249
Missense (PolyPhen)		56	55.265	1.0133		722
Synonymous	0.674	59	66.0	0.894	0.00000306	642
Loss of Function	2.03	7	15.6	0.447	7.55e-7	193

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.00029	0.00029	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Metal-dependent single-stranded DNA (ssDNA) exonuclease involved in mitochondrial genome maintenance. Has preference for 5'-3' exonuclease activity but is also capable of endoduclease activity on linear substrates. Necessary for maintenance of proper 7S DNA levels. Probably involved in mitochondrial DNA (mtDNA) repair, possibly via the processing of displaced DNA containing Okazaki fragments during RNA-primed DNA synthesis on the lagging strand or via processing of DNA flaps during long-patch base excision repair. Specifically binds 5-hydroxymethylcytosine (5hmC)-containing DNA in stem cells. {ECO:0000255|HAMAP- Rule:MF_03030, ECO:0000269|PubMed:23313956, ECO:0000269|PubMed:23358826}.;
Disease: DISEASE: Mitochondrial DNA depletion syndrome 11 (MTDPS11) [MIM:615084]: An autosomal recessive mitochondrial disorder characterized by onset in childhood or adulthood of progressive external ophthalmoplegia, muscle weakness and atrophy, exercise intolerance, and respiratory insufficiency due to muscle weakness. More variable features include spinal deformity, emaciation, and cardiac abnormalities. Skeletal muscle biopsies show deletion and depletion of mitochondrial DNA (mtDNA) with variable defects in respiratory chain enzyme activities. {ECO:0000269|PubMed:23313956}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0984

Intolerance Scores

RVIS EVS: 0.68
RVIS percentile EVS: 85.04

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium