The MLB2 c.154C>T (p.Arg52Cys) missense variant, commonly referred to as the "D" allele, has been described in at least one study in individuals with recurrent infections and low serum MBP levels in which it was found in a compound heterozygous state with another missense variant in one individual with a very low serum MBP level and in a homozygous state in another individual with no detectable serum MBP level (Summerfield et al. 1995). The p.Arg52Cys variant has also been investigated in healthy unrelated individuals with low or undetectable MBP levels (Madsen et al. 1994; Babovic-Vuksanovic et al. 1999) and found at a frequency of 0.05 in both the African and Caucasian populations in both a compound heterozygous state and a heterozygous state. Functional studies by Liu et al. (2012) showed that the p.Arg52Cys variant did not affect gene transcription or protein secretion, but did result in a lower level of oligomerization, a loss of ability to bind mannan, a reduced ability to bind to MASP1 and MASP2 and failed to activate the complement system. However, it should be noted that MBL deficiency is very common. The p.Arg52Cys variant is reported at a frequency of is 0.11111 in the Finnish population of the 1000 Genomes Project. While the allele frequency for this variant appears to be high, multiple studies referenced in this paragraph have shown a significant over-representation of this variant in individuals with low levels of mannose-binding lectin as compared to controls. Many individuals who carry MBL2 variants classified as pathogenic do not develop clinical complications. Based on the evidence, the p.Arg52Cys variant is classified as pathogenic for mannose-binding lectin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ClinVar Genomic variation as it relates to human health
NM_001378373.1(MBL2):c.154C>T (p.Arg52Cys)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1); Benign(2)
Pathogenic(1); Uncertain significance(1); Benign(2)
4 out of 6 submissions contributed to this 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.
6
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001378373.1(MBL2):c.154C>T (p.Arg52Cys)
Variation ID: 14352 Accession: VCV000014352.30
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q21.1 10: 52771482 (GRCh38) [ NCBI UCSC ] 10: 54531242 (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 Jan 6, 2017 Mar 22, 2025 Mar 26, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001378373.1:c.154C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001365302.1:p.Arg52Cys missense NM_000242.3:c.154C>T NP_000233.1:p.Arg52Cys missense NM_001378374.1:c.154C>T NP_001365303.1:p.Arg52Cys missense NC_000010.11:g.52771482G>A NC_000010.10:g.54531242G>A NG_008196.1:g.5219C>T LRG_154:g.5219C>T LRG_154t1:c.154C>T P11226:p.Arg52Cys - Protein change
- -
- Other names
-
R52C
- Canonical SPDI
- NC_000010.11:52771481:G:A
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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.
-
0.02716 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.05557
Exome Aggregation Consortium (ExAC) 0.05695
1000 Genomes Project 0.02716
1000 Genomes Project 30x 0.02748
Trans-Omics for Precision Medicine (TOPMed) 0.04630
The Genome Aggregation Database (gnomAD) 0.04964
- 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. |
|||
| MBL2 | - | - |
GRCh38 GRCh37 |
109 | 130 | |
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. |
|---|---|---|---|---|
| Conflicting classifications of pathogenicity (3) |
criteria provided, conflicting classifications
|
Mar 26, 2024 | RCV000015426.36 | |
| risk factor (1) |
no assertion criteria provided
|
Apr 1, 2019 | RCV000991134.3 | |
| Conflicting classifications of pathogenicity (2) |
criteria provided, conflicting classifications
|
Feb 9, 2024 | RCV002274881.24 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(Mar 26, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Mannose-binding lectin deficiency
Affected status: unknown
Allele origin:
germline
|
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Accession: SCV004806905.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
|
Benign
(Feb 09, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003453490.3
First in ClinVar: Feb 07, 2023 Last updated: Feb 25, 2025 |
|
|
|
Uncertain significance
(Jul 01, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002563004.18
First in ClinVar: Aug 23, 2022 Last updated: Mar 22, 2025 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Dec 11, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Mannose-binding lectin deficiency
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914462.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The MLB2 c.154C>T (p.Arg52Cys) missense variant, commonly referred to as the "D" allele, has been described in at least one study in individuals with recurrent … (more)
The MLB2 c.154C>T (p.Arg52Cys) missense variant, commonly referred to as the "D" allele, has been described in at least one study in individuals with recurrent infections and low serum MBP levels in which it was found in a compound heterozygous state with another missense variant in one individual with a very low serum MBP level and in a homozygous state in another individual with no detectable serum MBP level (Summerfield et al. 1995). The p.Arg52Cys variant has also been investigated in healthy unrelated individuals with low or undetectable MBP levels (Madsen et al. 1994; Babovic-Vuksanovic et al. 1999) and found at a frequency of 0.05 in both the African and Caucasian populations in both a compound heterozygous state and a heterozygous state. Functional studies by Liu et al. (2012) showed that the p.Arg52Cys variant did not affect gene transcription or protein secretion, but did result in a lower level of oligomerization, a loss of ability to bind mannan, a reduced ability to bind to MASP1 and MASP2 and failed to activate the complement system. However, it should be noted that MBL deficiency is very common. The p.Arg52Cys variant is reported at a frequency of is 0.11111 in the Finnish population of the 1000 Genomes Project. While the allele frequency for this variant appears to be high, multiple studies referenced in this paragraph have shown a significant over-representation of this variant in individuals with low levels of mannose-binding lectin as compared to controls. Many individuals who carry MBL2 variants classified as pathogenic do not develop clinical complications. Based on the evidence, the p.Arg52Cys variant is classified as pathogenic for mannose-binding lectin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Pathogenic
(Aug 01, 2006)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: literature only
|
MANNOSE-BINDING LECTIN DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035690.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2017 |
Comment on evidence:
Madsen et al. (1994) identified a third variant allele, the 'D' allele (rs5030737), in the collagen region of MBL2, and suggested that this variant could … (more)
Madsen et al. (1994) identified a third variant allele, the 'D' allele (rs5030737), in the collagen region of MBL2, and suggested that this variant could explain cases of MBL deficiency (MBLD; 614372) not determined by the other variants. The frequency of allele D was 0.05 in both African and Caucasian populations, but the allele was absent in Eskimos. Bodamer et al. (2006) genotyped 5 common polymorphisms, including the B, C, and D variants, of the MBL2 gene in 102 infants born before 36 weeks' gestation and 102 infants born at full term and found that the frequency of the D allele was significantly higher in preterm infants compared to term infants (p = 0.04). (less)
|
|
|
risk factor
(Apr 01, 2019)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: research
|
Cystic fibrosis
Affected status: yes
Allele origin:
germline
|
Center for Computational Genomics and Data Science, University of Alabama
Accession: SCV001142521.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Number of individuals with the variant: 2
Indication for testing: Cystic fibrosis
Zygosity: Single Heterozygote
Secondary finding: no
|
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:
The MLB2 c.154C>T (p.Arg52Cys) missense variant, commonly referred to as the "D" allele, has been described in at least one study in individuals with recurrent infections and low serum MBP levels in which it was found in a compound heterozygous state with another missense variant in one individual with a very low serum MBP level and in a homozygous state in another individual with no detectable serum MBP level (Summerfield et al. 1995). The p.Arg52Cys variant has also been investigated in healthy unrelated individuals with low or undetectable MBP levels (Madsen et al. 1994; Babovic-Vuksanovic et al. 1999) and found at a frequency of 0.05 in both the African and Caucasian populations in both a compound heterozygous state and a heterozygous state. Functional studies by Liu et al. (2012) showed that the p.Arg52Cys variant did not affect gene transcription or protein secretion, but did result in a lower level of oligomerization, a loss of ability to bind mannan, a reduced ability to bind to MASP1 and MASP2 and failed to activate the complement system. However, it should be noted that MBL deficiency is very common. The p.Arg52Cys variant is reported at a frequency of is 0.11111 in the Finnish population of the 1000 Genomes Project. While the allele frequency for this variant appears to be high, multiple studies referenced in this paragraph have shown a significant over-representation of this variant in individuals with low levels of mannose-binding lectin as compared to controls. Many individuals who carry MBL2 variants classified as pathogenic do not develop clinical complications. Based on the evidence, the p.Arg52Cys variant is classified as pathogenic for mannose-binding lectin deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Applying whole-genome sequencing in relation to phenotype and outcomes in siblings with cystic fibrosis. | Wilk MA | Cold Spring Harbor molecular case studies | 2020 | PMID: 32014855 |
| Mannose-binding lectin gene as a modifier of the cystic fibrosis phenotype in Argentinean pediatric patients. | Gravina LP | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society | 2015 | PMID: 25178872 |
| Mannose-binding lectin 2 gene polymorphism and lung damage in primary ciliary dyskinesia. | Pifferi M | Pediatric pulmonology | 2015 | PMID: 24753481 |
| Polymorphisms in the lectin pathway genes as a possible cause of early chronic Pseudomonas aeruginosa colonization in cystic fibrosis patients. | Haerynck F | Human immunology | 2012 | PMID: 22940091 |
| Mannan-binding lectin deficiency - Good news, bad news, doesn't matter? | Heitzeneder S | Clinical immunology (Orlando, Fla.) | 2012 | PMID: 22377282 |
| Defective activities, but not secretions, resulting from gene point mutations of human mannan-binding lectin. | Liu Y | Molecular medicine reports | 2012 | PMID: 22323042 |
| Use of a modeling framework to evaluate the effect of a modifier gene (MBL2) on variation in cystic fibrosis. | McDougal KE | European journal of human genetics : EJHG | 2010 | PMID: 20068595 |
| Complex two-gene modulation of lung disease severity in children with cystic fibrosis. | Dorfman R | The Journal of clinical investigation | 2008 | PMID: 18292811 |
| Evidence for an association between mannose-binding lectin 2 (MBL2) gene polymorphisms and pre-term birth. | Bodamer OA | Genetics in medicine : official journal of the American College of Medical Genetics | 2006 | PMID: 16912583 |
| Association of MBL gene polymorphisms with major bacterial infection in patients treated with high-dose chemotherapy and autologous PBSCT. | Horiuchi T | Genes and immunity | 2005 | PMID: 15674393 |
| Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. | Garred P | The Journal of clinical investigation | 1999 | PMID: 10449435 |
| Mannose-binding lectin (MBL) deficiency. Variant alleles in a midwestern population of the United States. | Babovic-Vuksanovic D | Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology | 1999 | PMID: 10071515 |
| Mannose binding protein gene mutations associated with unusual and severe infections in adults. | Summerfield JA | Lancet (London, England) | 1995 | PMID: 7707811 |
| A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein. | Madsen HO | Immunogenetics | 1994 | PMID: 8206524 |
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Text-mined citations for rs5030737 ...
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 Mar 22, 2025
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.