ClinVar Genomic variation as it relates to human health
NM_004531.5(MOCS2):c.226G>A (p.Gly76Arg)
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.
Pathogenic(2); Likely pathogenic(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004531.5(MOCS2):c.226G>A (p.Gly76Arg)
Variation ID: 419958 Accession: VCV000419958.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q11.2 5: 53102097 (GRCh38) [ NCBI UCSC ] 5: 52397927 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 27, 2017 Feb 14, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004531.5:c.226G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004522.1:p.Gly76Arg missense NM_176806.4:c.*146G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NC_000005.10:g.53102097C>T NC_000005.9:g.52397927C>T NG_008435.2:g.12672G>A - Protein change
- G76R
- Other names
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- Canonical SPDI
- NC_000005.10:53102096:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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MOCS2 | - | - |
GRCh38 GRCh37 |
310 | 390 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Aug 9, 2022 | RCV000479116.9 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 30, 2024 | RCV001731709.6 |
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
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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
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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
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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. |
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Likely pathogenic
(Sep 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP B
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001984789.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
This variant, also referred to as c.413G>A in the literature, has been previously reported in association with Molybdenum Cofactor Deficiency (PMID: 12754701, 22403017, 28900816, 21907887). … (more)
This variant, also referred to as c.413G>A in the literature, has been previously reported in association with Molybdenum Cofactor Deficiency (PMID: 12754701, 22403017, 28900816, 21907887). The c.226G>A variant is predicted by multiple in silico tools to damage or destroy the natural splice donor site of intron 4 and create a cryptic splice donor site 4 bp upstream of the natural one. If this variant does not alter splicing, it will result in the p.Gly76Arg missense change. The c.226G>A (p.Gly76Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0044% (11/250780) and thus is presumed to be rare. This variant is located within a large region of homozygosity (ROH) seen in this patient. Based on the available evidence, the c.226G>A (p.Gly76Arg) variant is classified as Likely Pathogenic. (less)
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Likely pathogenic
(Dec 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579812.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PM3, PM2_SUP, PP3
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Number of individuals with the variant: 1
Sex: female
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Uncertain significance
(Aug 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001533514.3
First in ClinVar: Mar 22, 2021 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 76 of the MOCS2B protein (p.Gly76Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 76 of the MOCS2B protein (p.Gly76Arg). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs780085174, gnomAD 0.04%). This missense change has been observed in individual(s) with molybdenum cofactor deficiency (PMID: 12754701). ClinVar contains an entry for this variant (Variation ID: 419958). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(Mar 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000568189.6
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Splice site variant of the last nucleotide of the exon in a gene for which loss-of-function is a known mechanism of disease, and splice predictors … (more)
Splice site variant of the last nucleotide of the exon in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect.; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; in addition, in silico splice predictors suggest this variant may lead to abnormal gene splicing, but in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 21031595, 28900816, 22403017, 12754701, 31201073, 21907887) (less)
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Uncertain significance
(Nov 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004236374.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004244367.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
Criteria applied: PM3_VSTR,PP3, PM2_SUP
Clinical Features:
Combined molybdoflavoprotein enzyme deficiency (present) , Abnormal basal ganglia morphology (present) , EEG with burst suppression (present) , Basal ganglia cysts (present) , Sulfite oxidase … (more)
Combined molybdoflavoprotein enzyme deficiency (present) , Abnormal basal ganglia morphology (present) , EEG with burst suppression (present) , Basal ganglia cysts (present) , Sulfite oxidase deficiency (present) , Abnormal cerebral morphology (present) , Hypotonia (present) , Increased circulating lactate concentration (present) , Myoclonic seizure (present) , Cerebral edema (present) , Epileptic encephalopathy (present) , Paralytic ileus (present) , Hematochezia (present) (less)
Sex: female
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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 |
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Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH. | Reiss J | Human mutation | 2003 | PMID: 12754701 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs780085174 ...
HelpRecord last updated May 12, 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.