ClinVar Genomic variation as it relates to human health
NM_000528.4(MAN2B1):c.1830+1G>C
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
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NM_000528.4(MAN2B1):c.1830+1G>C
Variation ID: 21207 Accession: VCV000021207.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 12655693 (GRCh38) [ NCBI UCSC ] 19: 12766507 (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 4, 2013 Oct 8, 2024 Sep 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000528.4:c.1830+1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001173498.2:c.1827+1G>C splice donor NC_000019.10:g.12655693C>G NC_000019.9:g.12766507C>G NG_008318.1:g.16085G>C - Protein change
- Other names
- IVS14DS, G-C, +1
- Canonical SPDI
- NC_000019.10:12655692:C:G
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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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00010
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 | ||
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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
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. |
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MAN2B1 | - | - |
GRCh38 GRCh37 |
1560 | 1735 |
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. |
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Pathogenic (13) |
criteria provided, multiple submitters, no conflicts
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Mar 15, 2024 | RCV000020364.35 | |
Pathogenic (1) |
criteria provided, single submitter
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May 20, 2017 | RCV000622767.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 20, 2024 | RCV001564933.7 |
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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Pathogenic
(Sep 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002014287.1
First in ClinVar: Nov 12, 2021 Last updated: Nov 12, 2021 |
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Pathogenic
(Apr 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: unknown
Allele origin:
inherited
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002099128.1 First in ClinVar: Feb 26, 2022 Last updated: Feb 26, 2022 |
Clinical Features:
Global developmental delay (present) , Neurodevelopmental delay (present) , Cerebral visual impairment (present) , Ureteropelvic junction obstruction (present) , Hydronephrosis (present) , Polymicrogyria (present) , … (more)
Global developmental delay (present) , Neurodevelopmental delay (present) , Cerebral visual impairment (present) , Ureteropelvic junction obstruction (present) , Hydronephrosis (present) , Polymicrogyria (present) , Ventricular septal defect (present) , Nystagmus (present) (less)
Secondary finding: no
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Pathogenic
(Nov 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002816992.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 15, 2024)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004191841.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Nov 25, 2019)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001364017.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MAN2B1 c.1830+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more)
Variant summary: MAN2B1 c.1830+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.3e-05 in 248630 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis (9.3e-05 vs 0.0016). c.1830+1G>C has been reported in the literature as one of the most common disease causing variants in multiple individuals affected with Alpha-Mannosidosis (example, Riise Stensland_2012, Berg_1999). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function were ascertained within the context of this evaluation. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002499236.1
First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
PVS1, PM2, PM3
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Pathogenic
(May 20, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742222.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian
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Pathogenic
(May 22, 2020)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002017213.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001588917.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 14 of the MAN2B1 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 14 of the MAN2B1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). This variant is present in population databases (rs80338677, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with mannosidosis (PMID: 9915946, 26048034). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS14+1G>C. ClinVar contains an entry for this variant (Variation ID: 21207). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002558049.2
First in ClinVar: Aug 04, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available, intron 14). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (24 heterozygotes, 0 homozygotes). (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0704 - Comparable variant has low previous evidence for pathogenicity (Borgwardt, L. et al. (2015); Riise Stensland, H. et al. (2012)). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar; Matlach, J. et al (2018)). (P) 1102 - Strong phenotype match. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(Sep 20, 2024)
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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: SCV001788179.5
First in ClinVar: Aug 19, 2021 Last updated: Oct 08, 2024 |
Comment:
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a … (more)
Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 9915946, 22161967, 31980526, 34429528, 38382588, 38107468) (less)
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Pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV002060327.2
First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022 |
Comment:
NM_000528.3(MAN2B1):c.1830+1G>C is a canonical splice variant classified as pathogenic in the context of alpha-mannosidosis. c.1830+1G>C has been observed in cases with relevant disease (PMID: 9915946, … (more)
NM_000528.3(MAN2B1):c.1830+1G>C is a canonical splice variant classified as pathogenic in the context of alpha-mannosidosis. c.1830+1G>C has been observed in cases with relevant disease (PMID: 9915946, 22161967). Functional assessments of this variant are not available in the literature. c.1830+1G>C has been observed in population frequency databases (gnomAD: FIN 0.03%). In summary, NM_000528.3(MAN2B1):c.1830+1G>C is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Mar 01, 2012)
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no assertion criteria provided
Method: literature only
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ALPHA-MANNOSIDOSIS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000056374.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 27, 2017 |
Comment on evidence:
In a study of 130 unrelated patients with alpha-mannosidosis (MANSA; 248500) from 30 countries, Riise Stensland et al. (2012) found that a G-to-C transversion in … (more)
In a study of 130 unrelated patients with alpha-mannosidosis (MANSA; 248500) from 30 countries, Riise Stensland et al. (2012) found that a G-to-C transversion in intron 14 (IVS14+1G-C) of the MAN2B1 gene (Berg et al., 1999) was present on 13 disease alleles, making it the second most common mutation after R750W (609458.0004). (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Alpha-mannosidosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001454353.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Deficiency of alpha-mannosidase
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000040751.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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
HelpText-mined citations for rs80338677 ...
HelpRecord last updated Oct 08, 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.