NDUFS1

NADH:ubiquinone oxidoreductase core subunit S1, the group of NADH:ubiquinone oxidoreductase core subunits

Basic information

Region (hg38): 2:206114816-206159509

Links

ENSG00000023228 ∙ NCBI:4719 ∙ OMIM:157655 ∙ HGNC:7707 ∙ Uniprot:P28331 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Leigh syndrome (Definitive), mode of inheritance: AR
• mitochondrial complex I deficiency, nuclear type 1 (Definitive), mode of inheritance: AR
• mitochondrial complex 1 deficiency, nuclear type 5 (Strong), mode of inheritance: AR
• mitochondrial complex I deficiency (Supportive), mode of inheritance: AR
• Leigh syndrome with leukodystrophy (Supportive), mode of inheritance: AR
• mitochondrial disease (Definitive), mode of inheritance: AR
• Leigh syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Mitochondrial complex I deficiency, nuclear type 5	AR	General	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	Biochemical; Cardiovascular; Gastrointestinal; Neurologic; Ophthalmologic	11743516; 11349233; 15824269; 16478720; 20382551; 21203893
Medical treatment (eg, riboflavin, ubiquinol) may be beneficial; Individuals may have cardiac involvement

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NDUFS1 gene.

• not provided (301 variants)
• Leigh syndrome (79 variants)
• Mitochondrial complex I deficiency, nuclear type 1 (72 variants)
• Mitochondrial complex 1 deficiency, nuclear type 5 (49 variants)
• Inborn genetic diseases (41 variants)
• not specified (33 variants)
• Mitochondrial complex I deficiency (11 variants)
• NDUFS1-related condition (4 variants)
• See cases (3 variants)
• Juvenile myopathy, encephalopathy, lactic acidosis AND stroke (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NDUFS1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	32	2	37
missense	1	12	132		1	146
nonsense	5	1	1			7
start loss			1			1
frameshift	4	5				9
inframe indel		2	2			4
splice donor/acceptor (+/-2bp)		5	2			7
splice region		1	5	5	1	12
non coding			24	62	61	147
Total	10	25	165	94	64

Highest pathogenic variant AF is 0.0000329

Variants in NDUFS1

This is a list of pathogenic ClinVar variants found in the NDUFS1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-206123108-T-A		Leigh syndrome • Mitochondrial complex I deficiency, nuclear type 1	Uncertain significance (Jan 13, 2018)
2-206123219-T-C		Leigh syndrome • Mitochondrial complex I deficiency, nuclear type 1	Uncertain significance (Jan 12, 2018)
2-206123247-G-A		Mitochondrial complex I deficiency, nuclear type 1 • Leigh syndrome	Uncertain significance (Jan 13, 2018)
2-206123319-T-G		Leigh syndrome • Mitochondrial complex I deficiency, nuclear type 1	Uncertain significance (Jan 12, 2018)
2-206123321-C-T		Mitochondrial complex I deficiency, nuclear type 1 • Leigh syndrome	Uncertain significance (Jan 12, 2018)
2-206123338-TA-T		Leigh syndrome • Mitochondrial complex I deficiency	Likely benign (Jun 14, 2016)
2-206123338-T-TA		Leigh syndrome • Mitochondrial complex I deficiency	Uncertain significance (Jun 14, 2016)
2-206123429-T-A		Leigh syndrome • Mitochondrial complex I deficiency, nuclear type 1	Uncertain significance (Jan 13, 2018)
2-206123452-T-C		Leigh syndrome • Mitochondrial complex I deficiency, nuclear type 1	Benign (Jan 12, 2018)
2-206123544-T-C		Leigh syndrome • Mitochondrial complex I deficiency, nuclear type 1	Uncertain significance (Jan 12, 2018)
2-206123611-A-C		Mitochondrial complex I deficiency, nuclear type 1 • Leigh syndrome	Benign/Likely benign (May 24, 2021)
2-206123624-A-G		Mitochondrial complex I deficiency, nuclear type 1 • Leigh syndrome	Uncertain significance (Jan 12, 2018)
2-206123681-C-T		Mitochondrial complex I deficiency, nuclear type 1 • Leigh syndrome	Uncertain significance (Jan 12, 2018)
2-206123726-T-C		Leigh syndrome • Mitochondrial complex I deficiency, nuclear type 1	Uncertain significance (Jan 12, 2018)
2-206123728-A-T		Leigh syndrome • Mitochondrial complex I deficiency, nuclear type 1	Benign (May 13, 2021)
2-206123747-G-A		Mitochondrial complex I deficiency, nuclear type 1 • Leigh syndrome	Uncertain significance (Jan 13, 2018)
2-206123759-A-C		Leigh syndrome • Mitochondrial complex I deficiency, nuclear type 1	Conflicting classifications of pathogenicity (Aug 30, 2021)
2-206123786-C-T		Mitochondrial complex I deficiency, nuclear type 1 • Leigh syndrome	Benign/Likely benign (May 20, 2021)
2-206123844-T-C		Leigh syndrome • Mitochondrial complex I deficiency, nuclear type 1	Conflicting classifications of pathogenicity (May 29, 2021)
2-206123849-C-A		Leigh syndrome • Mitochondrial complex I deficiency, nuclear type 1	Benign (May 13, 2021)
2-206123929-G-A		Leigh syndrome • Mitochondrial complex I deficiency, nuclear type 1	Benign/Likely benign (Jul 09, 2018)
2-206124027-A-G		Mitochondrial complex I deficiency, nuclear type 1 • Leigh syndrome	Benign/Likely benign (Jan 13, 2018)
2-206124034-A-G		Mitochondrial complex I deficiency, nuclear type 1 • Leigh syndrome	Uncertain significance (Jan 12, 2018)
2-206124055-T-G		Mitochondrial complex I deficiency, nuclear type 1 • Leigh syndrome	Uncertain significance (Jan 12, 2018)
2-206124091-A-AT		Mitochondrial complex I deficiency • Leigh syndrome	Uncertain significance (Jun 14, 2016)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NDUFS1	protein_coding	protein_coding	ENST00000455934	19	44787

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.63e-11	0.992	125667	0	81	125748	0.000322

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0751	413	409	1.01	0.0000204	4848
Missense in Polyphen		110	139.43	0.78892		1696
Synonymous	-0.407	139	133	1.04	0.00000623	1455
Loss of Function	2.53	23	40.3	0.570	0.00000217	467

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000800	0.000781
Ashkenazi Jewish	0.000198	0.000198
East Asian	0.000874	0.000816
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.000274	0.000273
Middle Eastern	0.000874	0.000816
South Asian	0.000464	0.000457
Other	0.00	0.00

dbNSFP

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 (By similarity). This is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme. It may form part of the active site crevice where NADH is oxidized. {ECO:0000250}.
• 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:11349233}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: 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);Oxidative phosphorylation - Homo sapiens (human);Parkinson,s disease - Homo sapiens (human);Metformin Pathway, Pharmacodynamic;Electron Transport Chain;Oxidative phosphorylation;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. (Consensus)

Recessive Scores

• pRec: 0.370

Intolerance Scores

• loftool: 0.208
• rvis_EVS: -0.89
• rvis_percentile_EVS: 10.43

Haploinsufficiency Scores

• pHI: 0.111
• hipred: N
• hipred_score: 0.229
• ghis: 0.600

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.988

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ndufs1
• Phenotype: vision/eye phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); homeostasis/metabolism phenotype

Gene ontology

• Biological process: mitochondrial electron transport, NADH to ubiquinone;apoptotic mitochondrial changes;mitochondrial respiratory chain complex I assembly;cellular respiration;ATP metabolic process;regulation of mitochondrial membrane potential;reactive oxygen species metabolic process
• Cellular component: mitochondrion;mitochondrial respiratory chain complex I;mitochondrial intermembrane space;mitochondrial matrix;myelin sheath;plasma membrane respiratory chain complex I
• Molecular function: NADH dehydrogenase activity;protein binding;NADH dehydrogenase (ubiquinone) activity;electron transfer activity;metal ion binding;2 iron, 2 sulfur cluster binding;4 iron, 4 sulfur cluster binding