NM_052845.4:c.556C>T

Variant names:

• chr12-109561068-G-A
• rs28941784
• NM_052845.4:c.556C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_052845.4(MMAB):​c.556C>T​(p.Arg186Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,525,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R186P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: MMAB NM_052845.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 1.64
• Publications: 27 publications found

Genes affected

MMAB (HGNC:19331): (metabolism of cobalamin associated B) This gene encodes a protein that catalyzes the final step in the conversion of vitamin B(12) into adenosylcobalamin (AdoCbl), a vitamin B12-containing coenzyme for methylmalonyl-CoA mutase. Mutations in the gene are the cause of vitamin B12-dependent methylmalonic aciduria linked to the cblB complementation group. Alternatively spliced transcript variants have been found. [provided by RefSeq, Apr 2011]

MMAB Gene-Disease associations (from GenCC):

• methylmalonic aciduria, cblB type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_052845.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-109561067-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2954625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 12-109561068-G-A is Pathogenic according to our data. Variant chr12-109561068-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMAB	NM_052845.4	c.556C>T	p.Arg186Trp	missense_variant	Exon 7 of 9	ENST00000545712.7	NP_443077.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMAB	ENST00000545712.7	c.556C>T	p.Arg186Trp	missense_variant	Exon 7 of 9	1	NM_052845.4	ENSP00000445920.1

Frequencies

GnomAD3 genomes AF: 0.000150 AC: 22 AN: 146782 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000476

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000285

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000140 AC: 35 AN: 249262 AF XY: 0.000111

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000496

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000278 AC: 383 AN: 1378920 Hom.: 0 Cov.: 36 AF XY: 0.000265 AC XY: 182 AN XY: 685538

African (AFR) AF: 0.0000967 AC: 3 AN: 31038

American (AMR) AF: 0.0000474 AC: 2 AN: 42190

Ashkenazi Jewish (ASJ) AF: 0.0000435 AC: 1 AN: 22970

East Asian (EAS) AF: 0.00 AC: 0 AN: 33574

South Asian (SAS) AF: 0.0000702 AC: 6 AN: 85502

European-Finnish (FIN) AF: 0.000135 AC: 6 AN: 44294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5286

European-Non Finnish (NFE) AF: 0.000336 AC: 356 AN: 1059386

Other (OTH) AF: 0.000165 AC: 9 AN: 54680

GnomAD4 genome AF: 0.000150 AC: 22 AN: 146918 Hom.: 0 Cov.: 30 AF XY: 0.000140 AC XY: 10 AN XY: 71552

African (AFR) AF: 0.0000248 AC: 1 AN: 40370

American (AMR) AF: 0.00 AC: 0 AN: 14728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 4484

South Asian (SAS) AF: 0.000475 AC: 2 AN: 4208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000285 AC: 19 AN: 66692

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.000269 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonic aciduria, cblB type Pathogenic:12 Other:1

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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). -

Jun 15, 2014

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with vitamin B12-responsive methylmalonic aciduria cblB type (MIM#251110). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 59 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated cobalamin adenosyltransferase domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with methylmalonic aciduria cblB type (PMID: 16410054) and regarded as pathogenic in ClinVar. It is usually associated with early onset (GeneReviews). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Site directed mutagenesis was used to introduce the human homologue substitution p.(Arg119Trp) in Thermoplasma acidophilum, which was shown to result in no enzyme activity (PMID: 15044458). (SP) 1205 - This variant has been shown to be maternally inherited. Mother was tested by Fulgent laboratory. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 01, 2021

Baumgartner lab, University Children's Hospital Zurich

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Dec 15, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:3

Apr 23, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jul 09, 2020

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jun 04, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

MMAB-related disorder Pathogenic:1

Jul 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. In summary, we classify the c.556C>T (p.Arg186Trp) variant as pathogenic. -

Methylmalonic acidemia Pathogenic:1

Feb 02, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.8	H;.
PhyloP100		1.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.5	D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MVP		1.0
MPC		0.85
ClinPred		1.0	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28941784; hg19: chr12-109998873; COSMIC: COSV57170516; COSMIC: COSV57170516;