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)
ClinVar Genomic variation as it relates to human health
NM_004531.5(MOCS2):c.226G>A (p.Gly76Arg)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(3); Uncertain significance(2)
Pathogenic(2); Likely pathogenic(3); Uncertain significance(2)
7 out of 8 submissions contributed to this classification
Help
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.
8
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004531.5(MOCS2):c.226G>A (p.Gly76Arg)
Variation ID: 419958 Accession: VCV000419958.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q11.2 5: 53102097 (GRCh38) [ NCBI UCSC ] 5: 52397927 (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 Apr 27, 2017 Apr 13, 2025 Oct 9, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide 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
- -
- Canonical SPDI
- NC_000005.10:53102096: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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
- 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. |
|||
| MOCS2 | Gene associated with autosomal recessive phenotype | No evidence available |
GRCh38 GRCh37 |
336 | 417 | |
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. |
|---|---|---|---|---|
| Conflicting classifications of pathogenicity (3) |
criteria provided, conflicting classifications
|
Jun 1, 2024 | RCV000479116.17 | |
| Conflicting classifications of pathogenicity (4) |
criteria provided, conflicting classifications
|
Oct 9, 2024 | RCV001731709.10 | |
|
MOCS2-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
May 2, 2024 | RCV004758020.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 02, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
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)
|
|
|
Uncertain significance
(Aug 09, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
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)
|
|
|
Likely pathogenic
(Sep 30, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP B
Affected status: yes
Allele origin:
germline
|
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)
|
|
|
Likely pathogenic
(Dec 16, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579812.2
First in ClinVar: Oct 15, 2022 Last updated: Apr 13, 2025
Comment:
ACMG criteria applied: PS4, PM3, PM2_SUP, PP3
|
Number of individuals with the variant: 1
Sex: female
|
|
|
Uncertain significance
(Nov 22, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004236374.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Oct 09, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004244367.4
First in ClinVar: Feb 14, 2024 Last updated: Apr 13, 2025 |
Comment:
Criteria applied: PM3_VSTR,PP3, PM2_SUP
Clinical Features:
Epileptic encephalopathy (present) , Abnormal basal ganglia morphology (present) , EEG with burst suppression (present) , Sulfite oxidase deficiency (present) , Increased circulating lactate concentration (present) , Hematochezia (present) , Hypotonia (present) , Combined molybdoflavoprotein enzyme deficiency (present) , Paralytic ileus (present) , Myoclonic seizure (present) , Basal ganglia cysts (present) , Abnormal cerebral morphology (present) , Cerebral edema (present)
Sex: female
|
|
|
Likely pathogenic
(Jun 01, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005075533.6
First in ClinVar: Jul 15, 2024 Last updated: Mar 22, 2025 |
Comment:
MOCS2: PM3:Strong, PM2, PP3
Number of individuals with the variant: 2
|
|
|
Pathogenic
(May 02, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
MOCS2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005360298.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The MOCS2 c.226G>A variant is predicted to result in the amino acid substitution p.Gly76Arg. This variant has also been described as c.413G>A based on alternate … (more)
The MOCS2 c.226G>A variant is predicted to result in the amino acid substitution p.Gly76Arg. This variant has also been described as c.413G>A based on alternate nomenclature outlined in Reiss and Hahnewald. 2011. PubMed ID: 21031595. This variant has been reported in the homozygous state in multiple individuals classified with severe molybdenum cofactor deficiency (Reiss and Johnson. 2003. PubMed ID: 12754701; Vijayakumar et al. 2011. PubMed ID: 21907887; Hinderhofer et al. 2017. PubMed ID: 28900816; Spiegel et al 2022. PubMed ID: 35192225). The c.226G nucleotide is the last nucleotide in exon 4 of the MOCS2 NM_004531 transcript, and the c.226G>A substitution is predicted by in silico splicing prediction programs to weaken the adjacent canonical splice donor site and increase the strength of a nearby cryptic splice donor site within exon 4, possibly leading to aberrant splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). Consistent with this observation, Reiss and Johnson reported that the c.226G>A substitution (using the c.413G>A alternate nomenclature) lead to the deletion of 4 base pairs in all MOCS2 transcripts, resulting in premature protein termination (see Table 2 in Reiss and Johnson. 2003. PubMed ID: 12754701). Based on these observations, we classify the c.226G>A (p.Gly76Arg) variant as pathogenic. (less)
|
Comment:
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). 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.
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). 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.
Comment:
Criteria applied: PM3_VSTR,PP3, PM2_SUP
Comment:
MOCS2: PM3:Strong, PM2, PP3
Comment:
The MOCS2 c.226G>A variant is predicted to result in the amino acid substitution p.Gly76Arg. This variant has also been described as c.413G>A based on alternate nomenclature outlined in Reiss and Hahnewald. 2011. PubMed ID: 21031595. This variant has been reported in the homozygous state in multiple individuals classified with severe molybdenum cofactor deficiency (Reiss and Johnson. 2003. PubMed ID: 12754701; Vijayakumar et al. 2011. PubMed ID: 21907887; Hinderhofer et al. 2017. PubMed ID: 28900816; Spiegel et al 2022. PubMed ID: 35192225). The c.226G nucleotide is the last nucleotide in exon 4 of the MOCS2 NM_004531 transcript, and the c.226G>A substitution is predicted by in silico splicing prediction programs to weaken the adjacent canonical splice donor site and increase the strength of a nearby cryptic splice donor site within exon 4, possibly leading to aberrant splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). Consistent with this observation, Reiss and Johnson reported that the c.226G>A substitution (using the c.413G>A alternate nomenclature) lead to the deletion of 4 base pairs in all MOCS2 transcripts, resulting in premature protein termination (see Table 2 in Reiss and Johnson. 2003. PubMed ID: 12754701). Based on these observations, we classify the c.226G>A (p.Gly76Arg) variant as pathogenic.
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. |
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 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)
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). 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.
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). 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.
Comment:
Criteria applied: PM3_VSTR,PP3, PM2_SUP
Comment:
MOCS2: PM3:Strong, PM2, PP3
Comment:
The MOCS2 c.226G>A variant is predicted to result in the amino acid substitution p.Gly76Arg. This variant has also been described as c.413G>A based on alternate nomenclature outlined in Reiss and Hahnewald. 2011. PubMed ID: 21031595. This variant has been reported in the homozygous state in multiple individuals classified with severe molybdenum cofactor deficiency (Reiss and Johnson. 2003. PubMed ID: 12754701; Vijayakumar et al. 2011. PubMed ID: 21907887; Hinderhofer et al. 2017. PubMed ID: 28900816; Spiegel et al 2022. PubMed ID: 35192225). The c.226G nucleotide is the last nucleotide in exon 4 of the MOCS2 NM_004531 transcript, and the c.226G>A substitution is predicted by in silico splicing prediction programs to weaken the adjacent canonical splice donor site and increase the strength of a nearby cryptic splice donor site within exon 4, possibly leading to aberrant splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). Consistent with this observation, Reiss and Johnson reported that the c.226G>A substitution (using the c.413G>A alternate nomenclature) lead to the deletion of 4 base pairs in all MOCS2 transcripts, resulting in premature protein termination (see Table 2 in Reiss and Johnson. 2003. PubMed ID: 12754701). Based on these observations, we classify the c.226G>A (p.Gly76Arg) variant as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Apr 13, 2025
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.