ClinVar Genomic variation as it relates to human health
NM_001378373.1(MBL2):c.161G>A (p.Gly54Asp)
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.
Uncertain significance(1); Benign(2); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001378373.1(MBL2):c.161G>A (p.Gly54Asp)
Variation ID: 14350 Accession: VCV000014350.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q21.1 10: 52771475 (GRCh38) [ NCBI UCSC ] 10: 54531235 (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 Jan 6, 2017 Aug 4, 2024 Jan 23, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001378373.1:c.161G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001365302.1:p.Gly54Asp missense NM_000242.3:c.161G>A NP_000233.1:p.Gly54Asp missense NM_001378374.1:c.161G>A NP_001365303.1:p.Gly54Asp missense NC_000010.11:g.52771475C>T NC_000010.10:g.54531235C>T NG_008196.1:g.5226G>A LRG_154:g.5226G>A LRG_154t1:c.161G>A P11226:p.Gly54Asp - Protein change
- Other names
- G54D
- Canonical SPDI
- NC_000010.11:52771474:C:T
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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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0.12200 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.11335
Trans-Omics for Precision Medicine (TOPMed) 0.11580
1000 Genomes Project 0.12200
1000 Genomes Project 30x 0.12274
Exome Aggregation Consortium (ExAC) 0.13887
The Genome Aggregation Database (gnomAD), exomes 0.14072
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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MBL2 | - | - |
GRCh38 GRCh37 |
105 | 125 |
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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Likely benign (3) |
criteria provided, single submitter
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Apr 5, 2022 | RCV000015424.26 | |
Benign (1) |
criteria provided, single submitter
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Oct 28, 2020 | RCV001777138.2 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 23, 2024 | RCV002274880.17 |
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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Benign
(Oct 28, 2020)
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criteria provided, single submitter
Method: research
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not specified
Affected status: unknown
Allele origin:
germline
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H3Africa Consortium
Study: H3Africa
Accession: SCV002014644.1 First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021 |
Comment:
While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.052, its frequency in African populations is >5%. This suggests that previous classifications of … (more)
While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.052, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. (less)
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Uncertain significance
(Dec 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002563003.14
First in ClinVar: Aug 23, 2022 Last updated: Aug 04, 2024 |
Comment:
MBL2: PS3:Moderate, PS4:Supporting
Number of individuals with the variant: 2
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Likely benign
(Apr 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mannose-binding lectin deficiency
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809273.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Benign
(Jan 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003515799.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
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Pathogenic
(Oct 01, 2004)
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no assertion criteria provided
Method: literature only
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MANNOSE-BINDING LECTIN DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035687.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2017 |
Comment on evidence:
In 3 unrelated children with recurrent infections, opsonization defect, and low serum MBL protein concentrations (MBLD; 614372), Sumiya et al. (1991) identified a homozygous 230G-A … (more)
In 3 unrelated children with recurrent infections, opsonization defect, and low serum MBL protein concentrations (MBLD; 614372), Sumiya et al. (1991) identified a homozygous 230G-A transition in the MBL2 gene, resulting in a gly54-to-asp (G54D) substitution. The change is known as the 'B' allele. The change occurs in the fifth collagen repeat of the protein, which the authors predicted may disrupt the collagen helix sufficiently to hinder MBL assembly and secretion by hepatocytes. Study of 16 members of the 3 families showed autosomal dominant co-inheritance of the G54D mutation and low serum MBL concentrations. Super et al. (1992) found that among more than 100 randomly selected patients 5% were homozygotes for asp54. They showed that recombinant MBL with the asp54 substitution can oligomerize to yield a functional protein of about 650 kD that binds ligand and functions as an opsonin. However, although the recombinant MBL could form hexamers and therefore, like serum MBL, would be expected to act as a surrogate for C1q in classical pathway activation, this function was defective. The results indicated that the G54D substitution does not account for a deficiency state, but instead suggested that MBL has 2 predominant allelic forms that have overlapping function and that differ only in their ability to activate the classical pathway of complement. By immunoassay, Lipscombe et al. (1992) found reduced serum MBL levels in individuals carrying the G54D change. However, 3 wildtype individuals had no detectable MBL protein. The G54D change showed a reduced capacity to activate complement through the MPB-initiated classical pathway. The authors suggested that both homozygous and heterozygous individuals would have reduced serum levels of the protein. In a study of 123 healthy Danish individuals, Garred et al. (1992) found that 93 (75.6%) were gly54 homozygotes, 28 (22.8%) were heterozygous, and 2 (1.6%) were asp54 homozygotes; the frequency of the asp54 allele was 0.13. The median MBL concentration in the group of subjects with the asp54 allele was 6.4 times lower than in the gly54 homozygous group (195 and 1234 microg/l, respectively); however, the range in plasma concentrations of MBL was wide and overlapped between the groups. MBL protein was detected in the 2 asp54 homozygotes (9 and 387 microg/L), and there was no difference in relative mass and biologic activity between the 2 forms of the protein. Garred et al. (1992) concluded that the asp54 allele is able to produce a functional MBL protein that can be detected in serum at low concentrations. In 2 adult patients with severe and unusual infections, Summerfield et al. (1995) identified homozygosity for the G54D change. A third patient was compound heterozygous for the G54D and R52C (154545.0003) changes. The authors concluded that MBL deficiency may confer a life-long risk of infection. Turner et al. (2000) used MBL polymorphisms in the indigenous Australian population to date the appearance of the MBL B allele. They found a paucity of MBL structural gene mutations in 2 population groups from geographically distinct regions. Of 293 individuals tested, 289 were wildtype, and 4 were heterozygous for either the B or D allele. In each individual with an MBL mutation, the HLA haplotype profile suggested some Caucasian admixture. The authors hypothesized that the B mutation probably arose between 50,000 and 20,000 years ago, and that its absence from the founder gene pool of indigenous Australians may also partly explain their vulnerability to intracellular infections such as tuberculosis. To test the hypothesis that a genetic predisposition to a proinflammatory state could favor the appearance of gestational diabetes mellitus (GDM), Megia et al. (2004) studied the R52C (154545.0003) and G54D polymorphisms of the MBL2 gene and plasma MBL levels from 105 consecutive women with GDM and 173 healthy pregnant women. They found an association between G54D and GDM (odds ratio = 2.03 (1.18-3.49); P less than 0.01), and this association remained significant when the presence of both mutated alleles was considered (odds ratio = 1.76 (1.04-2.96); P less than 0.05). GDM patients who carried the G54D mutation required insulin therapy more frequently and had heavier infants than GDM women homozygous for the wildtype allele. An inverse correlation in GDM patients between neonatal weight and plasma MBL levels was found, remaining significant after adjustment for confounding variables. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Mannose-binding lectin deficiency
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000607348.1
First in ClinVar: Oct 14, 2017 Last updated: Oct 14, 2017 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Observation 1: Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Myopia (present)
Age: 30-39 years
Sex: female
Testing laboratory: Illumina Clinical Services Laboratory,Illumina
Date variant was reported to submitter: 2014-10-24
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Hearing impairment (present)
Age: 50-59 years
Sex: male
Testing laboratory: Illumina Clinical Services Laboratory,Illumina
Date variant was reported to submitter: 2014-10-31
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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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Mannose-binding lectin gene polymorphisms are associated with gestational diabetes mellitus. | Megia A | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 15472209 |
Restricted polymorphism of the mannose-binding lectin gene of indigenous Australians. | Turner MW | Human molecular genetics | 2000 | PMID: 10888598 |
Mannose binding protein gene mutations associated with unusual and severe infections in adults. | Summerfield JA | Lancet (London, England) | 1995 | PMID: 7707811 |
Gene frequency and partial protein characterization of an allelic variant of mannan binding protein associated with low serum concentrations. | Garred P | Clinical and experimental immunology | 1992 | PMID: 1458688 |
High frequencies in African and non-African populations of independent mutations in the mannose binding protein gene. | Lipscombe RJ | Human molecular genetics | 1992 | PMID: 1304173 |
Distinct and overlapping functions of allelic forms of human mannose binding protein. | Super M | Nature genetics | 1992 | PMID: 1303250 |
Molecular basis of opsonic defect in immunodeficient children. | Sumiya M | Lancet (London, England) | 1991 | PMID: 1675710 |
Text-mined citations for rs1800450 ...
HelpRecord last updated Aug 04, 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.