NDUFA13

protein-coding

NADH:ubiquinone oxidoreductase subunit A13, the group of NADH:ubiquinone oxidoreductase supernumerary subunits

Gene summary

This gene encodes a subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), which functions in the transfer of electrons from NADH to the respiratory chain. The protein is required for complex I assembly and electron transfer activity. The protein binds the signal transducers and activators of transcription 3 (STAT3) transcription factor, and can function as a tumor suppressor. The human protein purified from mitochondria migrates at approximately 16 kDa. Transcripts originating from an upstream promoter and capable of expressing a protein with a longer N-terminus have been found, but their biological validity has not been determined. [provided by RefSeq, Oct 2009]

MANE transcript

NM_015965.7

Inheritance

AR, AD

ClinVar variants

P:8U:55B:20

Top phenotype

Thyroid carcinoma, Hurthle cell

gnomAD constraint

pLI —, LoF o/e 1.06

Max pathogenic AF

—

Genomic locus

chr19:19,515,736-19,529,054

External References & Databases

Ensembl (ENSG00000186010)

Transcript & Mutation Effects

hg38 • Region Span ~13.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFA13 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of October 12, 2020. This gene is also known as GRIM19. The NDUFA13 gene encodes NADH:ubiquinone oxidoreductase (complex I) subunit A13, which plays a role in complex I assembly and function within the mitochondria. Defects of this protein lead to complex I deficiency. The NDUFA13 gene was first reported in association with autosomal recessive Leigh syndrome spectrum in 2015 (PMID: 25901006). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three variants identified in two cases from two publications (PMID: 25901006, 32722639). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known protein interaction, functional alteration in patient cells, and animal models (PMIDs: 27509854, 25901006, 32722639, 15367666). 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 on October 12, 2020 (SOP Version 7).

mitochondrial complex I deficiency, nuclear type 28LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032632

Submitter: Ambry Genetics

thyroid Hurthle cell carcinomaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0011836

Submitter: Ambry Genetics

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFA13* and *NDUFA13*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 18, 2024. This gene is also known as *GRIM19*. The *NDUFA13* gene encodes NADH:ubiquinone oxidoreductase (complex I) subunit A13, which plays a role in complex I assembly and function within the mitochondria. Defects of this protein lead to complex I deficiency. The *NDUFA13* gene was first reported in relation to autosomal recessive *NDUFA13*-related primary mitochondrial disease in 2015 (PMID: 25901006). *NDUFA13* has been associated with one disease entity to date; mitochondrial complex I deficiency, nuclear type 28 [OMIM# 618249]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *NDUFA13*-related primary mitochondrial disease. Of note, *NDUFA13* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on October 12, 2020 (SOP v7), with a final classification of Moderate. This current curation for the association with *NDUFA13*-related primary mitochondrial disease includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three unique variants (two missense, one frameshift leading to a premature truncation) identified in two unrelated cases from two publications (PMIDs: 25901006, 32722639). Disease onset was early in life. Clinical features in the two reported individuals include LSS, developmental delay, chorea, seizures, spasticity, optic atrophy, sensorineural hearing loss, cardiomyopathy, failure to thrive, and cerebellar atrophy with basal ganglia lesions. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), functional alteration studies in non-patient cells (PMID: 27626371), and by an embryonic lethal mouse knockout model with evidence of complex I deficiency in blastocysts (PMID: 15367666). In summary, there is moderate evidence to support the relationship between *NDUFA13* and autosomal recessive *NDUFA13*-related primary mitochondrial disease. 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/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 18, 2024 (SOP Version 10).

mitochondrial complex I deficiency, nuclear type 28STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032632

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Thyroid carcinoma, Hurthle cellAD

Manifestation: Biochemical; Neurologic; Oncologic; Ophthalmologic

Intervention: Oncologic

Rationale: Surveillance and/or awareness of thyroid cancer risk may allow early diagnosis and treatment of neoplasms, which may improve outcomes

Comments: In Mitochondrial complex I deficiency, medical treatment (eg, riboflavin, ubiquinol) may be beneficial; Individuals may have cardiac involvement

Refs: 15841082; 25901006

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFA13 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 64

Inborn genetic diseasesTotal: 31

Mitochondrial complex I deficiency, nuclear type 28Total: 10

Hurthle cell carcinoma of thyroidTotal: 3

NDUFA13-related disorderTotal: 2

Clark-Baraitser syndromeTotal: 1

Mitochondrial complex I deficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015965.7. 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			1 clinvar	18 clinvar	1 clinvar	20
missense	2 clinvar	2 clinvar	48 clinvar		1 clinvar	53
nonsense						0
start loss			1 clinvar			1
frameshift	1 clinvar	2 clinvar	2 clinvar			5
splice donor/acceptor (+/-2bp)		1 clinvar	3 clinvar			4
Total	3	5	55	18	2	83

Highest pathogenic variant AF is 0.00004339175

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015965.7	RefSeq	NP_057049.5	5	MANE Select
ENST00000507754.9	Ensembl	ENSP00000423673.1	5	MANE Select
ENST00000428459.6	Ensembl	ENSP00000465129.1	4	Standard
ENST00000428459.7	Ensembl	ENSP00000465129.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Retrograde endocannabinoid signaling - Homo sapiens (human)
Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)
Huntington,s disease - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)

Biological Process

positive regulation of peptidase activity
negative regulation of cell growth
mitochondrial respiratory chain complex I assembly
cellular response to interferon-beta
positive regulation of cysteine-type endopeptidase activity involved in apoptotic process

Molecular Function

NADH dehydrogenase activity
protein binding
ATP binding
NADH dehydrogenase (ubiquinone) activity

Cellular Component

nucleoplasm
cytoplasm
mitochondrion
mitochondrial inner membrane
mitochondrial respirasome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000507754
Coding exons: 5
Length: 17741
Individuals with no LoFs: 125667
Homozygous LoFs: 0
Heterozygous LoFs: 38
Defined: 125705
p: 0.000151

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.904	121	96.1	1.26	0.00000664	923
Missense (PolyPhen)		54	38.568	1.4001		353
Synonymous	-1.19	48	38.6	1.24	0.00000280	273
Loss of Function	-0.153	8	7.55	1.06	3.31e-7	84

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.00050	0.00050	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00023	0.00021	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis (PubMed:27626371). Complex I functions in the transfer of electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone (PubMed:27626371). Involved in the interferon/all-trans-retinoic acid (IFN/RA) induced cell death. This apoptotic activity is inhibited by interaction with viral IRF1. Prevents the transactivation of STAT3 target genes. May play a role in CARD15-mediated innate mucosal responses and serve to regulate intestinal epithelial cell responses to microbes (PubMed:15753091). {ECO:0000269|PubMed:12628925, ECO:0000269|PubMed:12867595, ECO:0000269|PubMed:15753091, ECO:0000269|PubMed:27626371}.;
Disease: DISEASE: Hurthle cell thyroid carcinoma (HCTC) [MIM:607464]: A rare type of thyroid cancer accounting for only about 3-10% of all differentiated thyroid cancers. These neoplasms are considered a variant of follicular carcinoma of the thyroid and are referred to as follicular carcinoma, oxyphilic type. {ECO:0000269|PubMed:15841082}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Note=Defects in NDUFA13 are a cause of a mitochondrial complex I deficiency characterized by early onset hypotonia, dyskinesia and sensorial deficiencies, as well as a severe optic neuropathy. {ECO:0000269|PubMed:25901006}.;

Recessive Scores

pRec: 0.146

Intolerance Scores

LoFtool: 0.678
RVIS EVS: -0.01
RVIS percentile EVS: 53.19

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Indispensability pred.: E
Indispensability score: 0.998

Gene Damage Prediction

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