TMEM126B

protein-coding

transmembrane protein 126B, the group of Mitochondrial complex I assembly complex

Gene summary

This gene encodes a mitochondrial transmembrane protein which is a component of the mitochondrial complex I assembly complex. The encoded protein serves as an assembly factor that is required for formation of the membrane arm of the complex. It interacts with NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 13. Naturally occurring mutations in this gene are associated with isolated complex I deficiency. A pseudogene of this gene has been defined on chromosome 9. [provided by RefSeq, Apr 2017]

MANE transcript

NM_018480.7

Inheritance

ClinVar variants

P:20U:52B:30

Top phenotype

Mitochondrial complex I deficiency, nuclear type 29

gnomAD constraint

pLI —, LoF o/e 0.86

Max pathogenic AF

—

Genomic locus

chr11:85,628,573-85,636,539

External References & Databases

Ensembl (ENSG00000171204)

Transcript & Mutation Effects

hg38 • Region Span ~8.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex I deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

mitochondrial complex I deficiency, nuclear type 29DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032633

Submitter: G2P

mitochondrial complex I deficiency, nuclear type 29STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032633

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *TMEM126B* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of March 7, 2022. The *TMEM126B* gene encodes transmembrane protein 126B, which is a chaperone protein involved in the assembly of mitochondrial complex I. Defects of this protein lead to complex I deficiency, with variable onset of disease from soon after birth to adulthood. The* TMEM126B* gene was first reported in relation to primary mitochondrial disease in 2016 (PMID: 27374773). While various names have been given to the constellation of features seen in those with *TMEM126B*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *TMEM126B* 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 (2 missense, 1 frameshift, 1 stop-gained) identified in nine unrelated cases from four publications (PMIDs: 27374773, 27374774, 27290639, 29093663). The mechanism of pathogenicity appears to be loss of function. Of note, the c.635G>T (p.Gly212Val) variant, a proposed founder variant, has been identified in every case reported to date. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, functional alteration studies in patient and non-patient cells showing impaired mitochondrial function due to variants or gene knockdown, and rescue of the mitochondrial dysfunction in patient cells following expression of the wildtype protein (PMIDs: 27374773, 27374774, 29093663, 27977873, 22982022). In summary, there is definitive evidence to support the relationship between *TMEM126B* and primary mitochondrial disease. This relationship has been repeatedly 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 March 7, 2022 (SOP Version 8).

mitochondrial complex I deficiency, nuclear type 29STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032633

Submitter: PanelApp Australia

mitochondrial complex I deficiency, nuclear type 29MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032633

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 29AR

Manifestation: Biochemical; Cardiovascular; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: Among other findings, individuals have been described with hypertrophic cardiomyopathy, and awareness may allow prompt diagnosis and management

Refs: 27374773; 27374774

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMEM126B variants in ClinVar

8 Conditions Cataloged

not providedTotal: 85

Inborn genetic diseasesTotal: 34

TMEM126B-related disorderTotal: 14

Mitochondrial complex I deficiency, nuclear type 29Total: 12

not specifiedTotal: 8

Mitochondrial diseaseTotal: 2

Mitochondrial complex I deficiency, nuclear type 1Total: 2

Mitochondrial complex I deficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018480.7. 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				17 clinvar		17
missense		2 clinvar	50 clinvar	12 clinvar	1 clinvar	65
nonsense	2 clinvar					2
start loss						0
frameshift	5 clinvar	8 clinvar				13
splice donor/acceptor (+/-2bp)		3 clinvar	2 clinvar			5
Total	7	13	52	29	1	102

Highest pathogenic variant AF is 0.0014366546

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018480.7	RefSeq	NP_060950.3	5	MANE Select
ENST00000358867.11	Ensembl	ENSP00000351737.7	5	MANE Select
NM_001193537.3	RefSeq	NP_001180466.1	5	Standard
NM_001193538.3	RefSeq	NP_001180467.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Respiratory electron transport
The citric acid (TCA) cycle and respiratory electron transport
Metabolism
Complex I biogenesis
Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins.

Biological Process

biological_process
mitochondrial respiratory chain complex I assembly

Molecular Function

molecular_function
protein binding

Cellular Component

cellular_component
mitochondrion
mitochondrial inner membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358867
Coding exons: 5
Length: 7952
Individuals with no LoFs: 124797
Homozygous LoFs: 0
Heterozygous LoFs: 41
Defined: 124838
p: 0.000164

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.179	128	122	1.05	0.00000585	1502
Missense (PolyPhen)		22	29.521	0.74524		406
Synonymous	0.224	40	41.8	0.956	0.00000209	440
Loss of Function	0.338	6	6.96	0.862	2.87e-7	110

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0011	0.00099	notable
Latino/Admixed American	0.00016	0.00015	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.000028	0.000026	rare
South Asian	0.00065	0.00050	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Chaperone protein involved in the assembly of the mitochondrial NADH:ubiquinone oxidoreductase complex (complex I). Participates in constructing the membrane arm of complex I. {ECO:0000269|PubMed:24191001}.;

Recessive Scores

pRec: 0.0730

Intolerance Scores

LoFtool: 0.918
RVIS EVS: 0.39
RVIS percentile EVS: 76.05

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0656

Gene Damage Prediction

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