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

gnomAD frequency: 0.00014  dbSNP: rs28941784

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186017	SCV000238979	pathogenic	not provided	2022-03-24	criteria provided, single submitter	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)
Illumina Laboratory Services, Illumina	RCV000003241	SCV000375743	pathogenic	Methylmalonic aciduria, cblB type	2017-04-28	criteria provided, single submitter	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000296390	SCV000699780	pathogenic	Methylmalonic acidemia	2017-02-02	criteria provided, single submitter	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.
Eurofins Ntd Llc (ga)	RCV000186017	SCV000854910	pathogenic	not provided	2018-04-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003241	SCV000941899	pathogenic	Methylmalonic aciduria, cblB type	2024-12-03	criteria provided, single submitter	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.
Myriad Genetics, Inc.	RCV000003241	SCV001194103	pathogenic	Methylmalonic aciduria, cblB type	2019-12-20	criteria provided, single submitter	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.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000003241	SCV001251496	pathogenic	Methylmalonic aciduria, cblB type		criteria provided, single submitter	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).
AiLife Diagnostics, AiLife Diagnostics	RCV000186017	SCV002503451	pathogenic	not provided	2020-07-09	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000003241	SCV002581583	likely pathogenic	Methylmalonic aciduria, cblB type	2022-04-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000003241	SCV002806050	pathogenic	Methylmalonic aciduria, cblB type	2024-06-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512694	SCV003714842	pathogenic	Inborn genetic diseases	2021-06-04	criteria provided, single submitter	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.
Baylor Genetics	RCV000003241	SCV004193140	pathogenic	Methylmalonic aciduria, cblB type	2024-03-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000003241	SCV005087011	pathogenic	Methylmalonic aciduria, cblB type	2023-07-17	criteria provided, single submitter	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
OMIM	RCV000003241	SCV000023399	pathogenic	Methylmalonic aciduria, cblB type	2002-12-15	no assertion criteria provided	literature only
GeneReviews	RCV000003241	SCV000258526	not provided	Methylmalonic aciduria, cblB type		no assertion provided	literature only
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000003241	SCV000267127	pathogenic	Methylmalonic aciduria, cblB type	2014-06-15	no assertion criteria provided	research
Natera, Inc.	RCV000003241	SCV001459239	pathogenic	Methylmalonic aciduria, cblB type	2020-09-16	no assertion criteria provided	clinical testing
Baumgartner lab, University Children's Hospital Zurich	RCV000003241	SCV001738795	pathogenic	Methylmalonic aciduria, cblB type	2021-06-01	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398428	SCV004104087	pathogenic	MMAB-related disorder	2024-07-23	no assertion criteria provided	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.