ClinVar Genomic variation as it relates to human health
NM_000528.4(MAN2B1):c.2140T>C (p.Trp714Arg)
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.2140T>C (p.Trp714Arg)
Variation ID: 208284 Accession: VCV000208284.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 12650129 (GRCh38) [ NCBI UCSC ] 19: 12760943 (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 Feb 2, 2016 Feb 14, 2024 Jan 10, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000528.4:c.2140T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000519.2:p.Trp714Arg missense NM_001173498.2:c.2137T>C NP_001166969.1:p.Trp713Arg missense NC_000019.10:g.12650129A>G NC_000019.9:g.12760943A>G NG_008318.1:g.21649T>C O00754:p.Trp714Arg - Protein change
- W714R, W713R
- Other names
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- Canonical SPDI
- NC_000019.10:12650128:A: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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
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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MAN2B1 | - | - |
GRCh38 GRCh37 |
1533 | 1703 |
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
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
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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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Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 10, 2024 | RCV000206950.13 |
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
(Nov 10, 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: SCV002060027.2
First in ClinVar: Jan 15, 2022 Last updated: Dec 24, 2022 |
Comment:
NM_000528.3(MAN2B1):c.2140T>C(W714R) is a missense variant classified as likely pathogenic in the context of alpha-mannosidosis. W714R has been observed in cases with relevant disease (PMID: 9915946, … (more)
NM_000528.3(MAN2B1):c.2140T>C(W714R) is a missense variant classified as likely pathogenic in the context of alpha-mannosidosis. W714R has been observed in cases with relevant disease (PMID: 9915946, 22161967). Functional assessments of this variant are available in the literature (PMID: 15035660). Internal structural analysis of the variant is supportive of pathogenicity. W714R has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000528.3(MAN2B1):c.2140T>C(W714R) is a missense variant that has both functional and internal structural support for pathogenicity and 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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Likely pathogenic
(Jan 10, 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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Invitae
Accession: SCV001377537.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 714 of the MAN2B1 protein … (more)
This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 714 of the MAN2B1 protein (p.Trp714Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with alpha-mannosidosis (PMID: 9915946, 22161967). ClinVar contains an entry for this variant (Variation ID: 208284). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MAN2B1 protein function. Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 15035660). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Uncertain significance
(Jun 07, 2012)
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no assertion criteria provided
Method: literature only
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Deficiency of alpha-mannosidase
Affected status: yes
Allele origin:
germline
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ClinVar Staff, National Center for Biotechnology Information (NCBI)
Accession: SCV000243993.1
First in ClinVar: Feb 02, 2016 Last updated: Feb 02, 2016 |
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Likely pathogenic
(Jun 23, 2017)
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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: SCV002086912.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 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
HelpTitle | Author | Journal | Year | Link |
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Identification of 83 novel alpha-mannosidosis-associated sequence variants: functional analysis of MAN2B1 missense mutations. | Riise Stensland HM | Human mutation | 2012 | PMID: 22161967 |
Intracellular transport of human lysosomal alpha-mannosidase and alpha-mannosidosis-related mutants. | Hansen G | The Biochemical journal | 2004 | PMID: 15035660 |
Spectrum of mutations in alpha-mannosidosis. | Berg T | American journal of human genetics | 1999 | PMID: 9915946 |
http://web.expasy.org/variant_pages/VAR_003346.html | - | - | - | - |
Text-mined citations for rs864621993 ...
HelpRecord last updated Feb 20, 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.