Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microphthalmia/coloboma and skeletal dysplasia syndrome (MIM#615877). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. A change to a histidine has been reported in a family with colobomatous microphthalmia, and the change to a cysteine has been reported in two de novo individuals with bilateral anophthalmia, intellectual disability and rhizomelic skeletal dysplasia (ClinVar, PMID: 24906020). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic in ClinVar and has also been reported in a family with dominant coloboma with microcornea, cataracts and skeletal dysplasia (PMID: 25719200). (SP) 0903 - This variant has limited evidence for segregation with disease. This variant has been shown to segregate with disease in five affected family members with dominant coloboma with microcornea, cataracts and skeletal dysplasia (PMID: 25719200). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
ClinVar Genomic variation as it relates to human health
NM_006439.5(MAB21L2):c.151C>G (p.Arg51Gly)
Germline
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.
(5)
Help
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
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006439.5(MAB21L2):c.151C>G (p.Arg51Gly)
Variation ID: 427785 Accession: VCV000427785.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q31.3 4: 150583180 (GRCh38) [ NCBI UCSC ] 4: 151504332 (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 Jun 20, 2017 Nov 24, 2024 Oct 9, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001364905.1:c.6330+4868G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_006439.5:c.151C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006430.1:p.Arg51Gly missense NM_001199282.2:c.6330+4868G>C intron variant NM_001367550.1:c.6330+4868G>C intron variant NM_006726.4:c.6363+4868G>C intron variant NC_000004.12:g.150583180C>G NC_000004.11:g.151504332C>G NG_032855.1:g.437318G>C NG_042314.1:g.6256C>G LRG_1324:g.437318G>C LRG_1324t1:c.6330+4868G>C - Protein change
- R51G
- Other names
- -
- Canonical SPDI
- NC_000004.12:150583179:C:G
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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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| LRBA | - | - |
GRCh38 GRCh37 |
2022 | 2115 | |
| MAB21L2 | - | - |
GRCh38 GRCh37 |
- | 77 | |
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. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 9, 2024 | RCV000490802.5 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Colobomatous microphthalmia-rhizomelic dysplasia syndrome
Affected status: yes
Allele origin:
de novo
|
Centogene AG - the Rare Disease Company
Accession: SCV001426542.1
First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020 |
|
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Pathogenic
(Nov 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Colobomatous microphthalmia-rhizomelic dysplasia syndrome
Affected status: yes
Allele origin:
maternal
|
Daryl Scott Lab, Baylor College of Medicine
Accession: SCV004102711.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
|
|
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Pathogenic
(Oct 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Colobomatous microphthalmia-rhizomelic dysplasia syndrome
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005399792.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microphthalmia/coloboma and skeletal dysplasia syndrome (MIM#615877). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. A change to a histidine has been reported in a family with colobomatous microphthalmia, and the change to a cysteine has been reported in two de novo individuals with bilateral anophthalmia, intellectual disability and rhizomelic skeletal dysplasia (ClinVar, PMID: 24906020). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic in ClinVar and has also been reported in a family with dominant coloboma with microcornea, cataracts and skeletal dysplasia (PMID: 25719200). (SP) 0903 - This variant has limited evidence for segregation with disease. This variant has been shown to segregate with disease in five affected family members with dominant coloboma with microcornea, cataracts and skeletal dysplasia (PMID: 25719200). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
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Pathogenic
(Jan 01, 2015)
|
no assertion criteria provided
Method: literature only
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MICROPHTHALMIA/COLOBOMA AND SKELETAL DYSPLASIA SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000579393.1
First in ClinVar: Jun 20, 2017 Last updated: Jun 20, 2017 |
Comment on evidence:
In 5 affected members of a family with coloboma, microcornea, cataracts, and skeletal dysplasia (MCSKS; 615877), Deml et al. (2015) identified heterozygosity for a c.151C-G … (more)
In 5 affected members of a family with coloboma, microcornea, cataracts, and skeletal dysplasia (MCSKS; 615877), Deml et al. (2015) identified heterozygosity for a c.151C-G transversion in the MAB21L2 gene, resulting in an arg51-to-gly (R51G) substitution at a conserved residue. The mutation segregated with disease in the family and was not found in the Exome Variant Server, dbSNP, or 1000 Genomes Project databases. The proband's unaffected mother showed a low 'G' peak at c.151 in addition to the wildtype 'C' upon sequencing, suggesting low-level mosaicism for the mutation. Functional analysis in HLEB3 cells showed that the R51G mutant was present at levels approximately 32% of those of wildtype MAB21L2, and protein stability assays showed a more rapid decrease in the amount of mutant compared to the wildtype protein at all time points examined, suggesting reduced stability of the R51G mutant. In addition, wildtype MAB21L2 mRNA showed efficient rescue of ocular anomalies in zebrafish embryos homozygous for a mab21l2 frameshift mutation (see ANIMAL MODEL), whereas there was an absence of robust rescue by mutant mRNA (68% versus 14%). No dominant-negative effect for the R51G mutant allele was observed. (less)
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Pathogenic
(Sep 26, 2019)
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no assertion criteria provided
Method: clinical testing
|
Colobomatous microphthalmia-rhizomelic dysplasia syndrome
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133057.1
First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020 |
|
Comment:
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:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microphthalmia/coloboma and skeletal dysplasia syndrome (MIM#615877). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. A change to a histidine has been reported in a family with colobomatous microphthalmia, and the change to a cysteine has been reported in two de novo individuals with bilateral anophthalmia, intellectual disability and rhizomelic skeletal dysplasia (ClinVar, PMID: 24906020). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic in ClinVar and has also been reported in a family with dominant coloboma with microcornea, cataracts and skeletal dysplasia (PMID: 25719200). (SP) 0903 - This variant has limited evidence for segregation with disease. This variant has been shown to segregate with disease in five affected family members with dominant coloboma with microcornea, cataracts and skeletal dysplasia (PMID: 25719200). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
| Mutations in MAB21L2 result in ocular Coloboma, microcornea and cataracts. | Deml B | PLoS genetics | 2015 | PMID: 25719200 |
| Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations. | Rainger J | American journal of human genetics | 2014 | PMID: 24906020 |
Text-mined citations for rs587777512 ...
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 Nov 25, 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.