ClinVar Genomic variation as it relates to human health
NM_000528.4(MAN2B1):c.685C>T (p.Arg229Trp)
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.685C>T (p.Arg229Trp)
Variation ID: 208258 Accession: VCV000208258.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 12663781 (GRCh38) [ NCBI UCSC ] 19: 12774595 (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 Dec 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000528.4:c.685C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000519.2:p.Arg229Trp missense NM_001173498.2:c.685C>T NP_001166969.1:p.Arg229Trp missense NC_000019.10:g.12663781G>A NC_000019.9:g.12774595G>A NG_008318.1:g.7997C>T NG_015814.1:g.1978G>A O00754:p.Arg229Trp - Protein change
- R229W
- Other names
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- Canonical SPDI
- NC_000019.10:12663780:G:A
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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
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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
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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 |
1535 | 1705 |
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
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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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Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Dec 28, 2023 | RCV000206936.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 30, 2022 | RCV003238730.1 |
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. |
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Likely pathogenic
(May 10, 2017)
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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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Counsyl
Accession: SCV000800761.1
First in ClinVar: Feb 02, 2016 Last updated: Feb 02, 2016 |
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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: SCV002014509.1
First in ClinVar: Nov 12, 2021 Last updated: Nov 12, 2021 |
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Pathogenic
(Apr 14, 2022)
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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: SCV002511544.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
Variant summary: MAN2B1 c.685C>T (p.Arg229Trp) results in a non-conservative amino acid change located in the Glycoside hydrolase family 38, N-terminal domain (IPR000602) of the encoded … (more)
Variant summary: MAN2B1 c.685C>T (p.Arg229Trp) results in a non-conservative amino acid change located in the Glycoside hydrolase family 38, N-terminal domain (IPR000602) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251450 control chromosomes (gnomAD). c.685C>T has been reported in the literature in multiple individuals affected with Alpha-Mannosidosis (Rise Stensland_2012, Mkaouar_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Berg_2002, Rise Stensland_2012, Mkaouar_2021). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Jun 10, 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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DASA
Accession: SCV002526386.1
First in ClinVar: Jun 18, 2022 Last updated: Jun 18, 2022 |
Comment:
The c.685C>T;p.(Arg229Trp) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 208258; PMID: 26048034; 22161967; 11959458; … (more)
The c.685C>T;p.(Arg229Trp) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 208258; PMID: 26048034; 22161967; 11959458; 21505070) - PS4_moderate.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 11959458) - PS3_moderate. The variant is present at low allele frequencies population databases (rs763257568– gnomAD 0.0001314%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg229Trp) was detected in trans with a Pathogenic variant (PMID: 26048034) - PM3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
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Pathogenic
(Dec 28, 2023)
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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: SCV001225168.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 229 of the MAN2B1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 229 of the MAN2B1 protein (p.Arg229Trp). This variant is present in population databases (rs763257568, gnomAD 0.007%). This missense change has been observed in individual(s) with mannosidosis (PMID: 22161967, 26048034). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 208258). 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: 11959458, 22161967). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 30, 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: SCV003936757.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
Comment:
Published functional studies demonstrate a damaging effect with the presence of the variant resulting in a significant reduction in enzyme activity (Riise Stensland et al., … (more)
Published functional studies demonstrate a damaging effect with the presence of the variant resulting in a significant reduction in enzyme activity (Riise Stensland et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11959458, 35871018, 22161967, 21505070, 34614013, 26048034) (less)
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Pathogenic
(Oct 22, 2023)
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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: SCV004191843.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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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: SCV000243964.1
First in ClinVar: Feb 02, 2016 Last updated: Feb 02, 2016 |
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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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Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment. | Mkaouar R | PloS one | 2021 | PMID: 34614013 |
Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation. | Borgwardt L | Orphanet journal of rare diseases | 2015 | PMID: 26048034 |
Identification of 83 novel alpha-mannosidosis-associated sequence variants: functional analysis of MAN2B1 missense mutations. | Riise Stensland HM | Human mutation | 2012 | PMID: 22161967 |
Molecular and cellular characterization of novel {alpha}-mannosidosis mutations. | Kuokkanen E | Human molecular genetics | 2011 | PMID: 21505070 |
alpha-Mannosidosis in the guinea pig: cloning of the lysosomal alpha-mannosidase cDNA and identification of a missense mutation causing alpha-mannosidosis. | Berg T | Biochimica et biophysica acta | 2002 | PMID: 11959458 |
http://web.expasy.org/variant_pages/VAR_068042.html | - | - | - | - |
Text-mined citations for rs763257568 ...
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.