NDUFS2

protein-coding

NADH:ubiquinone oxidoreductase core subunit S2, the group of NADH:ubiquinone oxidoreductase core subunits

Gene summary

The protein encoded by this gene is a core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Mammalian mitochondrial complex I is composed of at least 43 different subunits, 7 of which are encoded by the mitochondrial genome, and the rest are the products of nuclear genes. The iron-sulfur protein fraction of complex I is made up of 7 subunits, including this gene product. Complex I catalyzes the NADH oxidation with concomitant ubiquinone reduction and proton ejection out of the mitochondria. Mutations in this gene are associated with mitochondrial complex I deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

MANE transcript

NM_001377299.1

Inheritance

AR, Mitochondrial

ClinVar variants

P:18U:117B:51

Top phenotype

Mitochondrial complex I deficiency, nuclear type 6; Leber-like hereditary optic neuropathy, autosomal recessive 2

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr1:161,197,104-161,214,723

External References & Databases

Ensembl (ENSG00000158864)

Transcript & Mutation Effects

hg38 • Region Span ~17.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex I deficiency, nuclear type 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032611

Submitter: Ambry Genetics

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFS2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 18, 2024. *NDUFS2* encodes NADH:ubiquinone oxidoreductase (complex I) iron-sulfur (Fe-S) protein 2, a core subunit of complex I. Defects of this protein lead to complex I deficiency. *NDUFS2* was first reported in relation to autosomal recessive primary mitochondrial disease in 2001 (PMID: 11220739). While various names have been given to the constellation of features seen in those with *NDUFS2*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *NDUFS2* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *NDUFS2* was previously curated by this GCEP on April 9, 2021 (SOP Version 7) as having a Definitive association with autosomal recessive Leigh syndrome spectrum (LSS). The scope of this current curation encompassed cases of primary mitochondrial disease, which includes cases with LSS. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 12 variants (11 unique missense variants and a frameshift variant expected to result in protein truncation) in eight probands from fives publications (PMIDs: 11220739, 20819849, 22036843, 28031252, 31411514). Clinical features in affected individuals include Leigh syndrome spectrum, optic atrophy, lactic acidosis, cardiomyopathy, and hepatic involvement, and there is at least one reported case with clinical features consistent with Leber Hereditary Optic Neuropathy (PMIDs: 20819849, 22036843, 28031252, 31411514). The mechanism of disease is loss of function. This gene-disease association is also supported by its known biochemical functional, functional alternation in HEK293 cells with *NDUFS2* knockout, as well as model systems in *C.elegans* and mice (PMIDs: 27509854, 33744462, 18178500, 34732887, 31297047, 112788282). In summary, there is definitive evidence to support the relationship between *NDUFS2* 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 January 18, 2024 (SOP Version 10).

mitochondrial complex I deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

Leber hereditary optic neuropathySUPPORTIVE

Inheritance Pattern: Mitochondrial

Disease ID:MONDO:0010788

Submitter: Orphanet

mitochondrial complex I deficiency, nuclear type 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032611

Submitter: Labcorp Genetics (formerly Invitae)

Leigh syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFS2 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of November 23, 2020. The NDUFS2 gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit S2. Defects of this protein lead to complex I deficiency. The NDUFS2 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2001 (PMID: 11220739). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 6 variants in 5 cases from 3 publications (PMIDs: 11220739, 20819849, 22036843). Of note, the c.875T>C (p.Met292Thr) variant is speculated to be a hypomorphic allele (found in 2 homozygotes in gnomAD at the time of this gene review). 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 interactions, expression, functional alterations in patient cells, and model organisms (PMIDs: 27509854, 25613900, 14749350, 29526616, 31297047). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 23, 2020 (SOP Version 7).

mitochondrial complex I deficiency, nuclear type 6DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032611

Submitter: G2P

mitochondrial complex I deficiency, nuclear type 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032611

Submitter: PanelApp Australia

mitochondrial complex I deficiency, nuclear type 6LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032611

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 6; Leber-like hereditary optic neuropathy, autosomal recessive 2 AR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Neurologic; Ophthalmologic

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

Comments: In Mitochondrial complex I deficiency, nuclear type 5, medical treatment (eg, riboflavin, ubiquinol) may be beneficial, and individuals may have cardiac involvement

Refs: 11743516; 11220739; 20819849; 22036843; 28031252

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFS2 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 179

Inborn genetic diseasesTotal: 46

not specifiedTotal: 42

Mitochondrial complex I deficiency, nuclear type 6Total: 36

Mitochondrial complex I deficiency, nuclear type 1Total: 28

NDUFS2-related disorderTotal: 19

Leber-like hereditary optic neuropathy, autosomal recessive 2Total: 6

Leber optic atrophyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001377299.1. 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			9 clinvar	44 clinvar		53
missense	3 clinvar	5 clinvar	103 clinvar	6 clinvar	1 clinvar	118
nonsense	2 clinvar	3 clinvar				5
start loss						0
frameshift	1 clinvar	1 clinvar	1 clinvar			3
splice donor/acceptor (+/-2bp)		3 clinvar	4 clinvar			7
Total	6	12	117	50	1	186

Highest pathogenic variant AF is 0.0000316

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 84 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001377299.1	RefSeq	NP_001364228.1	14	MANE Select
ENST00000676972.1	Ensembl	ENSP00000503117.1	14	MANE Select
NM_001166159.2	RefSeq	NP_001159631.1	13	Standard
NM_001377298.1	RefSeq	NP_001364227.1	14	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

mitochondrial electron transport, NADH to ubiquinone
response to oxidative stress
mitochondrial respiratory chain complex I assembly
mitochondrial ATP synthesis coupled electron transport

Molecular Function

NADH dehydrogenase activity
protein binding
NADH dehydrogenase (ubiquinone) activity
electron transfer activity
ubiquitin protein ligase binding

Cellular Component

nucleoplasm
mitochondrion
mitochondrial respiratory chain complex I
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367993
Coding exons: 14
Length: 17292
Individuals with no LoFs: 125722
Homozygous LoFs: 0
Heterozygous LoFs: 26
Defined: 125748
p: 0.000103

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.47	192	259	0.742	0.0000153	2994
Missense (PolyPhen)		62	122.48	0.50619		1343
Synonymous	-1.18	108	93.4	1.16	0.00000476	919
Loss of Function	3.50	11	32.5	0.338	0.00000210	320

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000070	0.000070	rare
South Asian	0.00023	0.00023	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) that is believed to belong to the minimal assembly required for catalysis. 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:12611891). {ECO:0000269|PubMed:12611891}.;
Disease: DISEASE: Mitochondrial complex I deficiency (MT-C1D) [MIM:252010]: A disorder of the mitochondrial respiratory chain that causes a wide range of clinical manifestations from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. {ECO:0000269|PubMed:11220739}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.419

Intolerance Scores

LoFtool: 0.0524
RVIS EVS: 0.49
RVIS percentile EVS: 79.38

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.981

Gene Damage Prediction

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