ClinVar Genomic variation as it relates to human health
NM_176806.4(MOCS2):c.3G>A (p.Met1Ile)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_176806.4(MOCS2):c.3G>A (p.Met1Ile)
Variation ID: 813890 Accession: VCV000813890.5
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q11.2 5: 53109727 (GRCh38) [ NCBI UCSC ] 5: 52405557 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 1, 2020 Feb 14, 2024 May 18, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_004531.5:c.-646G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
5 prime UTR NM_176806.4:c.3G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_789776.1:p.Met1Ile missense initiator codon variant NC_000005.10:g.53109727C>T NC_000005.9:g.52405557C>T NG_008435.2:g.5042G>A - Protein change
- M1I
- Other names
- NM_176806.4(MOCS2):c.3G>A
- p.Met1Ile
- Canonical SPDI
- NC_000005.10:53109726:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
LOC129993881 | - | - | - | GRCh38 | - | 37 |
MOCS2 | - | - |
GRCh38 GRCh37 |
309 | 389 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 25, 2023 | RCV001004857.4 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 18, 2023 | RCV002549261.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Likely pathogenic
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002318501.2
First in ClinVar: Apr 02, 2022 Last updated: Sep 03, 2023 |
Comment:
Start-lost: reinitiation of translation may occur at a downstream alternate start codon but still result in a loss or disruption of normal protein function as … (more)
Start-lost: reinitiation of translation may occur at a downstream alternate start codon but still result in a loss or disruption of normal protein function as there have been pathogenic variants reported upstream of the alterante start codon . The variant was co-segregated with Molybdenum cofactor deficiency B in multiple affected family members (PMID: 27146152). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Cerebellar hypoplasia (present) , Ectopia lentis (present) , Global developmental delay (present)
|
|
Likely pathogenic
(Jan 25, 2023)
|
criteria provided, single submitter
Method: curation
|
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164335.3
First in ClinVar: Mar 01, 2020 Last updated: Sep 03, 2023 |
Comment:
The homozygous p.Met1Ile variant in MOCS2 was identified by our study in one individual with neurologic anomalies. The p.Met1Ile variant in MOCS2 has been previously … (more)
The homozygous p.Met1Ile variant in MOCS2 was identified by our study in one individual with neurologic anomalies. The p.Met1Ile variant in MOCS2 has been previously reported in 3 unrelated individuals with molybdenum cofactor deficiency B (‚Äã‚ÄãPMID: 27146152, PMID: 10053004, PMID: 27289259) and segregated with disease in 2 affected relatives from one family (PMID: 27146152), but has been identified in 0.0007% (1/152212) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1273139451). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. The three unrelated affected individuals previously reported were homozygotes (‚Äã‚ÄãPMID: 27146152, PMID: 10053004, PMID: 27289259), which increases the likelihood that the p.Met1Ile variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 813890) with conflicting interpretations of pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, c.2T>G (p.Met1Arg), has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 587508). This variant is located in the first amino acid and obliterates the methionine initiation codon. The next in-frame methionine is at amino acid residue 34 and there are 19 reported pathogenic or likely pathogenic variants in ClinVar upstream of this downstream methionine. Loss of function of the MOCS2 gene is an established disease mechanism in autosomal recessive molybdenum cofactor deficiency B. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive molybdenum cofactor deficiency B. ACMG/AMP Criteria applied: PVS1_Moderate, PM2_Supporting, PM5_Supporting, PM3, PP1 (Richards 2015). (less)
|
|
Pathogenic
(May 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV003525824.3
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of the initiator codon alters MOCS2A gene expression (PMID: 10053003). … (more)
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of the initiator codon alters MOCS2A gene expression (PMID: 10053003). ClinVar contains an entry for this variant (Variation ID: 813890). This variant is also known as M1I. Disruption of the initiator codon has been observed in individuals with molybdenum cofactor deficiency (PMID: 10053004, 27146152, 27289259). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the MOCS2A mRNA. There are no downstream in-frame methionine residues; therefore, it is expected to result in an absent or disrupted protein product. Loss-of-function variants in MOCS2A are known to be pathogenic (PMID: 21031595). (less)
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Molybdenum cofactor and isolated sulphite oxidase deficiencies: Clinical and molecular spectrum among Egyptian patients. | Zaki MS | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2016 | PMID: 27289259 |
Utility of whole exome sequencing for the early diagnosis of pediatric-onset cerebellar atrophy associated with developmental delay in an inbred population. | Megahed H | Orphanet journal of rare diseases | 2016 | PMID: 27146152 |
Molybdenum cofactor deficiency: Mutations in GPHN, MOCS1, and MOCS2. | Reiss J | Human mutation | 2011 | PMID: 21031595 |
Human molybdopterin synthase gene: genomic structure and mutations in molybdenum cofactor deficiency type B. | Reiss J | American journal of human genetics | 1999 | PMID: 10053004 |
Human molybdopterin synthase gene: identification of a bicistronic transcript with overlapping reading frames. | Stallmeyer B | American journal of human genetics | 1999 | PMID: 10053003 |
Text-mined citations for rs1273139451 ...
HelpRecord last updated Mar 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.