NM_052845.4(MMAB):c.556C>T (p.Arg186Trp) AND Methylmalonic aciduria, cblB type

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (12 submissions)
Last evaluated:: Jan 28, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000003241.32

Allele description

NM_052845.4(MMAB):c.556C>T (p.Arg186Trp)

Gene:

MMAB:metabolism of cobalamin associated B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.11

Genomic location:

Preferred name:

NM_052845.4(MMAB):c.556C>T (p.Arg186Trp)

Other names:

p.R186W:CGG>TGG

HGVS:

NC_000012.12:g.109561068G>A
NG_007096.1:g.17430C>T
NM_052845.4:c.556C>TMANE SELECT
NP_443077.1:p.Arg186Trp
NP_443077.1:p.Arg186Trp
NC_000012.11:g.109998873G>A
NM_052845.3:c.556C>T
NR_038118.2:n.667C>T
Q96EY8:p.Arg186Trp
p.R186W

Protein change:

R186W; ARG186TRP

Links:

UniProtKB: Q96EY8#VAR_017205; OMIM: 607568.0001; dbSNP: rs28941784

NCBI 1000 Genomes Browser:

rs28941784

Molecular consequence:

NM_052845.4:c.556C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_038118.2:n.667C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Methylmalonic aciduria, cblB type
Synonyms:: METHYLMALONIC ACIDURIA, VITAMIN B12-RESPONSIVE, DUE TO DEFECT IN SYNTHESIS OF ADENOSYLCOBALAMIN, cblB TYPE; Methylmalonic acidemia cblB type; Vitamin B12-responsive methylmalonic acidemia type cblB
Identifiers:: MONDO: MONDO:0009614; MedGen: C1855102; Orphanet: 28; Orphanet: 79311; OMIM: 251110

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000023399	OMIM	no assertion criteria provided	Pathogenic (Dec 15, 2002)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000258526	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000267127	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital - ORGANIC ACIDURIAS	no assertion criteria provided	Pathogenic (Jun 15, 2014)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000375743	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 28, 2017)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 22614770, 21048060, 16439175, 19625202, 24059531, 16410054, 23707710, 12471062 Citation Link,
SCV000941899	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12471062, 16410054, 16439175, 19625202, 28492532
SCV001194103	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 20, 2019)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 19625202, 16439175, 12471062, 16410054, 17957493, 20696242, 22614770, 24059531 Citation Link,
SCV001251496	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	research	PubMed (3) [See all records that cite these PMIDs] 16410054, 20301409, 25741868
SCV001459239	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001738795	Baumgartner lab, University Children's Hospital Zurich	no assertion criteria provided	Pathogenic (Jun 1, 2021)	germline	clinical testing
SCV002581583	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 5, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002806050	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004193140	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 3, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	1	not provided	not provided	not provided	not provided	research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing, literature only, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Variable dietary management of methylmalonic acidemia: metabolic and energetic correlations.

Hauser NS, Manoli I, Graf JC, Sloan J, Venditti CP.

Am J Clin Nutr. 2011 Jan;93(1):47-56. doi: 10.3945/ajcn.110.004341. Epub 2010 Nov 3.

PubMed [citation]

PMID:: 21048060
PMCID:: PMC3001598

High resolution melting analysis of the MMAB gene in cblB patients and in those with undiagnosed methylmalonic aciduria.

Illson ML, Dempsey-Nunez L, Kent J, Huang Q, Brebner A, Raff ML, Watkins D, Gilfix BM, Wittwer CT, Rosenblatt DS.

Mol Genet Metab. 2013 Sep-Oct;110(1-2):86-9. doi: 10.1016/j.ymgme.2013.04.020. Epub 2013 May 4.

PubMed [citation]

PMID:: 23707710

See all PubMed Citations (13)

Details of each submission

From OMIM, SCV000023399.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000258526.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital - ORGANIC ACIDURIAS, SCV000267127.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000375743.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000941899.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001194103.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS, SCV001251496.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (3)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From Natera, Inc., SCV001459239.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baumgartner lab, University Children's Hospital Zurich, SCV001738795.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002581583.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002806050.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004193140.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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