NDUFS7

protein-coding

NADH:ubiquinone oxidoreductase core subunit S7, the group of NADH:ubiquinone oxidoreductase core subunits

Gene summary

This gene encodes a protein that is a subunit of one of the complexes that forms the mitochondrial respiratory chain. This protein is one of over 40 subunits found in complex I, the nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase. This complex functions in the transfer of electrons from NADH to the respiratory chain, and ubiquinone is believed to be the immediate electron acceptor for the enzyme. Mutations in this gene cause Leigh syndrome due to mitochondrial complex I deficiency, a severe neurological disorder that results in bilaterally symmetrical necrotic lesions in subcortical brain regions. [provided by RefSeq, Jul 2008]

MANE transcript

NM_024407.5

Inheritance

ClinVar variants

P:22U:67B:111

Top phenotype

Mitochondrial complex I deficiency, nuclear type 3; Leigh syndrome

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr19:1,383,527-1,395,589

External References & Databases

Ensembl (ENSG00000115286)

Transcript & Mutation Effects

hg38 • Region Span ~12.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex I deficiency, nuclear type 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032608

Submitter: G2P

mitochondrial complex I deficiency, nuclear type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032608

Submitter: PanelApp Australia

mitochondrial complex I deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100133

Submitter: Orphanet

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NDUFS7* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of April 15, 2024. The *NDUFS*7 gene encodes encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit S7. Defects of this protein lead to complex I deficiency. *NDUFS7* was first reported in relation to autosomal recessive primary mitochondrial disease in 1999 (Triepels et al 2001; PMID: 10360771). While various names have been given to the constellation of features seen in those with *NDUFS7*-related disorders, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NDUFS7 phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Of note, *NDUFS7* was first curated by this Expert Panel for its association with Leigh syndrome spectrum (LSS) on August 21, 2019 (SOP V6), with a final classification of Moderate. This current curation for the association with primary mitochondrial disease includes the four cases included in the LSS curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three variants (two missense and one deep intronic variant resulting in generation of a cryptic exon and protein truncation) in six probands from five publications (PMIDs: 10360771, 17604671, 17275378, 22644603, 30369941). Clinical features in affected individuals include LSS, developmental delay, developmental regression, ataxia, seizures, hemiplegia, ophthalmoplegia, and lactic acidosis. Ragged red fibers were seen on muscle biopsy and complex I deficiency was noted in muscle and skin fibroblasts. The mechanism of disease is loss of function This gene-disease association is also supported by the known biochemical function of *NDUFS7* as a subunit of complex I, functional alternation in patient fibroblast cells, and several model systems (fruit fly, fungi, canine, embryonic lethal mouse model; PMIDs: 27509854, 30429455, 30972103, 12049648, 15956670, 27626380, 38316835). In summary, there is definitive evidence to support the relationship between *NDUFS7* 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 April 15, 2024 (SOP Version 10).

mitochondrial complex I deficiency, nuclear type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032608

Submitter: Labcorp Genetics (formerly Invitae)

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between NDUFS7 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of August 21, 2019. The NDUFS7 gene encodes the NADH:ubiquinone oxidoreductase (complex I) core subunit S7. Defects of this protein lead to complex I deficiency. The NDUFS7 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 1999 (PMID: 10360771). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included two unique variants identified in four cases from three publications (PMIDs: 10360771, 17604671, 22644603). 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, functional alteration in patient cells, and animal models (PMIDs: 15269216, 30429455, 30972103, 27509854). 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 August 21, 2019 (SOP Version 7).

Clinical Genomic Database (CGD)

Mitochondrial complex I deficiency, nuclear type 3; Leigh syndromeAR

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: Medical treatment (eg, riboflavin, ubiquinol) may be beneficial; Individuals may have cardiac involvement

Refs: 10330338; 11743516; 17275378; 17604671

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NDUFS7 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 283

not specifiedTotal: 60

Inborn genetic diseasesTotal: 32

Leigh syndromeTotal: 18

Mitochondrial complex I deficiency, nuclear type 3Total: 18

Mitochondrial complex I deficiency, nuclear type 1Total: 12

NDUFS7-related disorderTotal: 11

Exertional Heat IllnessTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024407.5. 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			3 clinvar	106 clinvar		109
missense	2 clinvar	6 clinvar	60 clinvar	5 clinvar		73
nonsense	2 clinvar	1 clinvar	2 clinvar			5
start loss	1 clinvar					1
frameshift		3 clinvar				3
splice donor/acceptor (+/-2bp)		7 clinvar	2 clinvar			9
Total	5	17	67	111	0	200

Highest pathogenic variant AF is 0.00008492374

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024407.5	RefSeq	NP_077718.3	8	MANE Select
ENST00000233627.14	Ensembl	ENSP00000233627.9	8	MANE Select
NM_001363602.2	RefSeq	NP_001350531.1	8	Standard
ENST00000313408.11	Ensembl	ENSP00000364262.5	7	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
aerobic respiration
electron transport coupled proton transport
mitochondrial respiratory chain complex I assembly

Molecular Function

protease binding
NADH dehydrogenase activity
protein binding
NADH dehydrogenase (ubiquinone) activity
oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor

Cellular Component

mitochondrial respiratory chain complex I
mitochondrial matrix
neuron projection
neuronal cell body
synaptic membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000233627
Coding exons: 8
Length: 12058
Individuals with no LoFs: 125425
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125436
p: 0.0000438

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.991	121	156	0.777	0.0000121	1358
Missense (PolyPhen)		40	68.929	0.58031		630
Synonymous	-1.73	80	62.6	1.28	0.00000567	423
Loss of Function	2.98	1	12.3	0.0814	6.29e-7	127

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

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. {ECO:0000305|PubMed:12611891}.;
Disease: DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:10360771}. Note=The disease is caused by mutations affecting the gene represented in this entry.; 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:10330338}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.127
RVIS EVS: -0.18
RVIS percentile EVS: 39.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.996

Gene Damage Prediction

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