GeneBe

MOCS1

protein-coding

molybdenum cofactor synthesis 1, the group of Radical S-adenosylmethionine domain containing

Gene summary

Molybdenum cofactor biosynthesis is a conserved pathway leading to the biological activation of molybdenum. The protein encoded by this gene is involved in this pathway. This gene was originally thought to produce a bicistronic mRNA with the potential to produce two proteins (MOCS1A and MOCS1B) from adjacent open reading frames. However, only the first open reading frame (MOCS1A) has been found to encode a protein from the putative bicistronic mRNA, whereas additional splice variants are likely to produce a fusion between the two open reading frames. This gene is defective in patients with molybdenum cofactor deficiency, type A. A related pseudogene has been identified on chromosome 16. [provided by RefSeq, Nov 2017]

MANE transcript

NM_001358530.2

Inheritance

AR

ClinVar variants

P:90U:302B:188

Top phenotype

Molybdenum cofactor deficiency, type A

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr6:39,899,578-39,934,551

External References & Databases

Ensembl (ENSG00000124615)NCBI Gene (4337)OMIM (603707)HGNC:7190GenCCUniProt (Q9NZB8)AlphaFoldClinVar (MOCS1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~35.0 kb
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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

sulfite oxidase deficiency due to molybdenum cofactor deficiency type ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009643

Submitter: Labcorp Genetics (formerly Invitae)

sulfite oxidase deficiency due to molybdenum cofactor deficiency type ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009643

Submitter: ClinGen

*MOCS1* was first reported in relation to autosomal recessive molybdenum cofactor deficiency A (MOCODA, MIM:252150) in 1998 (Reiss et al., PMID: 9731530). MOCODA is characterized by refractory neonatal seizures, dysmorphic features, ocular lens dislocation, and a characteristic urinary profile indicative of an underlying biochemical dysfunction (PMID:33017596). The underlying mechanism is a failure to synthesize molybdenum cofactor, leading to loss of function of the enzymes sulfite oxidase, xanthine oxidase, and aldehyde oxidase (PMID:33017596). Six variants (four missense, one frameshift, and one canonical splice-site) that have been reported in eight probands in four publications (PMIDs: 9731530, 9634514, 9921896, 29274890) are included in this curation. Co-segregation with disease was observed in a large consanguineous kindred (PMID:9634514). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be biallelic loss of function. The *MOCS1* gene encodes two functional enzymes, MOCS1A and MOCS1B, that participate in sequential steps of molybdenum cofactor synthesis (PMID:33017596). Variants affecting either enzyme individually or both in combination are sufficient to cause MOCODA. This gene-disease association is also supported by in vitro functional assays and a mouse model (PMID: 12471057, 17236133, 33017596). Alternative splicing of the *MOCS1* transcript leads to the generation of two functional enzymes, the monomeric MOCS1A and the hexameric MOCS1B. Both proteins are imported into the mitochondrial matrix, where they sequentially catalyze the first and second steps of molybdenum cofactor synthesis (PMID: 33017596). *MOCS1*-deficient mice recapitulate both the developmental and biochemical phenotypes observed in MOCODA patients (PMID:12471057). These phenotypes can be rescued by lentiviral transfection with a human *MOCS1* expression construct (PMID:17236133). In summary, *MOCS1* is definitively associated with autosomal recessive molybdenum cofactor deficiency A. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on April 8th, 2022 (SOP Version 8).

sulfite oxidase deficiency due to molybdenum cofactor deficiency type ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009643

Submitter: G2P

sulfite oxidase deficiency due to molybdenum cofactor deficiency type ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009643

Submitter: PanelApp Australia

sulfite oxidase deficiency due to molybdenum cofactor deficiency type ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009643

Submitter: Ambry Genetics

sulfite oxidase deficiency due to molybdenum cofactor deficiency type ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009643

Submitter: Natera

Clinical Genomic Database (CGD)

Molybdenum cofactor deficiency, type AAR

Manifestation: Biochemical; Neurologic; Ophthalmologic

Intervention: Biochemical

Rationale: The disorder can have severe neurologic sequelae, and the use of substitution therapy (with IV-administered purified cyclic pyranopterin monophosphate) has been reported as showing benefit in biochemical parameters as well as clinical/neurologic manifestations

Refs: 9731530; 10053004; 10327149; 16021469; 20385644; 21031595; 38627985; 39488078Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MOCS1 variants in ClinVar

9 Conditions Cataloged
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type ATotal: 681
not providedTotal: 93
Inborn genetic diseasesTotal: 84
not specifiedTotal: 50
MOCS1-related disorderTotal: 47
Intellectual disabilityTotal: 6
Combined molybdoflavoprotein enzyme deficiencyTotal: 3
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001358530.2. 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.

EffectPLPVUSLBBSum
synonymous
14
clinvar
167
clinvar
3
clinvar
 184
missense
2
clinvar
8
clinvar
279
clinvar
16
clinvar
2
clinvar
 307
nonsense
12
clinvar
8
clinvar
2
clinvar
 22
start loss
2
clinvar
 2
frameshift
31
clinvar
12
clinvar
5
clinvar
 48
splice donor/acceptor (+/-2bp)
3
clinvar
14
clinvar
 17
Total48423021835580

Highest pathogenic variant AF is 0.00008991055

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001358530.2RefSeqNP_001345459.111MANE Select
ENST00000340692.10EnsemblENSP00000344794.511MANE Select
NM_001075098.4RefSeqNP_001068566.110Standard
NM_001358529.2RefSeqNP_001345458.110Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Folate biosynthesis - Homo sapiens (human)
  • Metabolism
  • Molybdenum cofactor biosynthesis
  • Metabolism of water-soluble vitamins and cofactors
  • Metabolism of vitamins and cofactors

Biological Process

  • Mo-molybdopterin cofactor biosynthetic process
  • molybdopterin cofactor biosynthetic process

Molecular Function

  • GTP binding
  • metal ion binding
  • 4 iron, 4 sulfur cluster binding
  • GTP 3',8'-cyclase activity
  • cyclic pyranopterin monophosphate synthase activity

Cellular Component

  • nucleus
  • cytosol
  • molybdopterin synthase complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000373186
Coding exons
9
Length
34937
Individuals with no LoFs
125697
Homozygous LoFs
0
Heterozygous LoFs
51
Defined
125748
p
0.000203
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.6212572301.120.00001462501
Missense (PolyPhen)9695.4241.0061020
Synonymous-0.1339694.41.020.00000552791
Loss of Function1.301218.00.6680.00000106200

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000560.00055rare
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish0.000810.00079rare
East Asian0.000110.00011rare
Finnish0.0000920.000092rare
European (Non-Finnish)0.000200.00020rare
South Asian0.0000980.000098rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Isoform MOCS1A and isoform MOCS1B probably form a complex that catalyzes the conversion of 5'-GTP to cyclic pyranopterin monophosphate (cPMP). MOCS1A catalyzes the cyclization of GTP to (8S)-3',8-cyclo-7,8-dihydroguanosine 5'- triphosphate and MOCS1B catalyzes the subsequent conversion of (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate to cPMP. {ECO:0000269|PubMed:11891227}.;

Recessive Scores

pRec
0.135

Intolerance Scores

LoFtool
0.144
RVIS EVS
0.11
RVIS percentile EVS
62.1

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.168

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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