ClinVar Genomic variation as it relates to human health
NM_052845.4(MMAB):c.556C>T (p.Arg186Trp)
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_052845.4(MMAB):c.556C>T (p.Arg186Trp)
Variation ID: 3095 Accession: VCV000003095.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.11 12: 109561068 (GRCh38) [ NCBI UCSC ] 12: 109998873 (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 Feb 28, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_052845.4:c.556C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_443077.1:p.Arg186Trp missense NR_038118.2:n.667C>T non-coding transcript variant NC_000012.12:g.109561068G>A NC_000012.11:g.109998873G>A NG_007096.1:g.17430C>T Q96EY8:p.Arg186Trp - Protein change
- R186W
- Other names
- p.R186W:CGG>TGG
- Canonical SPDI
- NC_000012.12:109561067: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00011
The Genome Aggregation Database (gnomAD) 0.00014
1000 Genomes Project 30x 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00015
The Genome Aggregation Database (gnomAD), exomes 0.00014
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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MMAB | - | - |
GRCh38 GRCh37 |
454 | 549 |
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/Likely pathogenic (12) |
criteria provided, multiple submitters, no conflicts
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Jan 28, 2024 | RCV000003241.32 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 24, 2022 | RCV000186017.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 2, 2017 | RCV000296390.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 28, 2023 | RCV003398428.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 4, 2021 | RCV002512694.8 |
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
(Feb 02, 2017)
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criteria provided, single submitter
Method: clinical testing
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Methylmalonic acidemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699780.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
Variant summary: The MMAB c.556C>T (p.Arg186Trp) variant located in the Adenosycobalamin biosnthesis domain (via InterPro) causes an alteration of a non-conserved nucleotide, which 4/4 in … (more)
Variant summary: The MMAB c.556C>T (p.Arg186Trp) variant located in the Adenosycobalamin biosnthesis domain (via InterPro) causes an alteration of a non-conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest was found in 17/120070 control chromosomes at a frequency of 0.0001416, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMAB variant (0.0013944). Multiple publications cite the variant in affected individuals as homozygotes and compound heterozygotes and has been indicated to be a known common disease mutation (Lerner-Ellis_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Apr 23, 2018)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000854910.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Dec 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Methylmalonic aciduria, cblB type
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001194103.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_052845.3(MMAB):c.556C>T(R186W) is classified as pathogenic in the context of methylmalonic acidemia, cblB type. Sources cited for classification include the following: PMID 19625202, 16439175, 12471062, 16410054, … (more)
NM_052845.3(MMAB):c.556C>T(R186W) is classified as pathogenic in the context of methylmalonic acidemia, cblB type. Sources cited for classification include the following: PMID 19625202, 16439175, 12471062, 16410054, 17957493, 20696242, 22614770 and 24059531. Classification of NM_052845.3(MMAB):c.556C>T(R186W) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Jul 09, 2020)
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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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AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002503451.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
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Pathogenic
(Jun 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003714842.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The c.556C>T (p.R186W) alteration is located in exon 7 (coding exon 7) of the MMAB gene. This alteration results from a C to T substitution … (more)
The c.556C>T (p.R186W) alteration is located in exon 7 (coding exon 7) of the MMAB gene. This alteration results from a C to T substitution at nucleotide position 556, causing the arginine (R) at amino acid position 186 to be replaced by a tryptophan (W). This mutation has been reported in the compound heterozygous and homozygous states in multiple individuals with methylmalonic aciduria cblB complementation type (O'Shea, 2012; Nizon, 2013; Brasil, 2018). This mutation significantly disrupts the affinity between MMAB and adenosylcobalamin (Dobson, 2002; Zhang, 2006; Lerner-Ellis, 2006; Zhang, 2009). Based on the available evidence, this alteration is classified as pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Mar 24, 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: SCV000238979.15
First in ClinVar: Jul 18, 2015 Last updated: Mar 04, 2023 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21048060, 34915869, … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21048060, 34915869, 31260114, 20696242, 16410054, 12471062, 18251506, 19625202, 16439175, 17957493, 31525265) (less)
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Pathogenic
(Aug 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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MMAB-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004104087.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MMAB c.556C>T variant is predicted to result in the amino acid substitution p.Arg186Trp. This variant has been reported to be one of the most … (more)
The MMAB c.556C>T variant is predicted to result in the amino acid substitution p.Arg186Trp. This variant has been reported to be one of the most common causes of autosomal recessive methylmalonic acidemia, cblB type (e.g., Dobson et al. 2002. PubMed ID: 12471062; Lerner-Ellis et al. 2006. PubMed ID: 16410054; Forny et al. 2019. PubMed ID: 31260114). A different substitution at the same amino acid (p.Arg186Gln) has also been reported as a pathogenic MMAB variant (e.g., Lerner-Ellis et al. 2006. PubMedID: 16410054). The p.Arg186 amino acid is one of four invariant residues that make up the surface of the cob(I)alamin adenosyltransferase enzyme cobalamin binding cleft, and is thought to potentially interact with cobalamin (Schubert and Hill. 2006. PubMed ID: 17176040). Functional studies also indicate that the p.Arg186Trp substitution may affect normal enzyme oligomerization (Brasil et al. 2018. PubMed ID: 29197662). This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-109998873-G-A). In summary, we classify the c.556C>T (p.Arg186Trp) variant as pathogenic. (less)
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Pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Methylmalonic aciduria, cblB type
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000375743.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The MMAB c.556C>T (p. Arg186Trp) missense variant has been reported in six studies in which it is found in a total of 29 methylmalonic acidemia … (more)
The MMAB c.556C>T (p. Arg186Trp) missense variant has been reported in six studies in which it is found in a total of 29 methylmalonic acidemia (MMA) patients, including 15 homozygotes, 13 compound heterozygotes, and one heterozygote in whom a second variant was not identified (Dobson et al. 2002; Lerner-Ellis et al. 2006; Hauser et al. 2011; O'Shea et al. 2012; Illson et al. 2013; Nizon et al. 2013). The variant was present in a heterozygous state in four of 120 non-cblB cell lines, absent from 100 control alleles, and is reported at a frequency of 0.00017 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies suggest that the p.Arg186Trp variant results in an unstable protein and disrupts affinity binding between MMAB and adenosylcobalamin (Zhang et al. 2006; Zhang et al. 2009). Based on the collective evidence, the p.Arg186Trp variant is classified as pathogenic for methylmalonic acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Vitamin B12-responsive methylmalonic acidemia type cblB
Affected status: no
Allele origin:
germline
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251496.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
The MMAB c.556C>T (p.R186W) variant is frequently observed in individuals with methylmalonic aciduria (MMA) and is associated with an early onset of disease symptoms (PMID: … (more)
The MMAB c.556C>T (p.R186W) variant is frequently observed in individuals with methylmalonic aciduria (MMA) and is associated with an early onset of disease symptoms (PMID: 16410054, 20301409). (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Apr 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Methylmalonic aciduria, cblB type
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581583.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(May 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Methylmalonic aciduria, cblB type
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002806050.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Oct 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Methylmalonic aciduria, cblB type
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004193140.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Methylmalonic aciduria, cblB type
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000941899.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 186 of the MMAB protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 186 of the MMAB protein (p.Arg186Trp). This variant is present in population databases (rs28941784, gnomAD 0.02%). This missense change has been observed in individuals with MMAB-related conditions (PMID: 12471062, 16410054). ClinVar contains an entry for this variant (Variation ID: 3095). 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) performed at Invitae indicates that this missense variant is expected to disrupt MMAB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MMAB function (PMID: 16439175, 19625202). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 15, 2002)
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no assertion criteria provided
Method: literature only
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METHYLMALONIC ACIDURIA, cblB TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000023399.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Among 6 MMA patients with methylmalonic aciduria of the cblB type (251110), Dobson et al. (2002) determined that 2 were homozygous for a 556C-T transition … (more)
Among 6 MMA patients with methylmalonic aciduria of the cblB type (251110), Dobson et al. (2002) determined that 2 were homozygous for a 556C-T transition in the MMAB gene, which was predicted to result in an arg186-to-trp (R186W) substitution. In vitro uptake assays determined the adenosyl-Cbl levels in fibroblasts of these patients to be more than 4% of control cells. Three other patients were compound heterozygotes who each carried 1 of these mutant alleles. The allele frequency among 120 control cell lines was 1 of 60. (less)
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Pathogenic
(Jun 15, 2014)
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no assertion criteria provided
Method: research
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Methylmalonic aciduria, cblB type
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital
Study: ORGANIC ACIDURIAS
Accession: SCV000267127.1 First in ClinVar: Apr 15, 2016 Last updated: Apr 15, 2016 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Methylmalonic aciduria cblB type
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001459239.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(Jun 01, 2021)
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no assertion criteria provided
Method: clinical testing
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Methylmalonic aciduria, cblB type
Affected status: yes
Allele origin:
germline
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Baumgartner lab, University Children's Hospital Zurich
Accession: SCV001738795.1
First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Methylmalonic aciduria, cblB type
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000258526.2
First in ClinVar: Oct 11, 2015 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
HelpTitle | Author | Journal | Year | Link |
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Isolated Methylmalonic Acidemia. | Adam MP | - | 2022 | PMID: 20301409 |
Liver neoplasms in methylmalonic aciduria: An emerging complication. | Forny P | Journal of inherited metabolic disease | 2019 | PMID: 31260114 |
New perspectives for pharmacological chaperoning treatment in methylmalonic aciduria cblB type. | Brasil S | Biochimica et biophysica acta. Molecular basis of disease | 2018 | PMID: 29197662 |
Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias. | Nizon M | Orphanet journal of rare diseases | 2013 | PMID: 24059531 |
High resolution melting analysis of the MMAB gene in cblB patients and in those with undiagnosed methylmalonic aciduria. | Illson ML | Molecular genetics and metabolism | 2013 | PMID: 23707710 |
Neurocognitive phenotype of isolated methylmalonic acidemia. | O'Shea CJ | Pediatrics | 2012 | PMID: 22614770 |
Variable dietary management of methylmalonic acidemia: metabolic and energetic correlations. | Hauser NS | The American journal of clinical nutrition | 2011 | PMID: 21048060 |
Different altered pattern expression of genes related to apoptosis in isolated methylmalonic aciduria cblB type and combined with homocystinuria cblC type. | Jorge-Finnigan A | Biochimica et biophysica acta | 2010 | PMID: 20696242 |
Ligand-binding by catalytically inactive mutants of the cblB complementation group defective in human ATP:cob(I)alamin adenosyltransferase. | Zhang J | Molecular genetics and metabolism | 2009 | PMID: 19625202 |
Methylmalonic acidaemia: examination of genotype and biochemical data in 32 patients belonging to mut, cblA or cblB complementation group. | Merinero B | Journal of inherited metabolic disease | 2008 | PMID: 17957493 |
Impact of cblB mutations on the function of ATP:cob(I)alamin adenosyltransferase in disorders of vitamin B12 metabolism. | Zhang J | Molecular genetics and metabolism | 2006 | PMID: 16439175 |
Mutation and biochemical analysis of patients belonging to the cblB complementation class of vitamin B12-dependent methylmalonic aciduria. | Lerner-Ellis JP | Molecular genetics and metabolism | 2006 | PMID: 16410054 |
Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. | Lerner-Ellis JP | Nature genetics | 2006 | PMID: 16311595 |
Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria. | Dobson CM | Human molecular genetics | 2002 | PMID: 12471062 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MMAB | - | - | - | - |
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Text-mined citations for rs28941784 ...
HelpRecord last updated Apr 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.