Total submissions: 18
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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, |
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, |
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 |
RCV000186017 | SCV000854910 | pathogenic | not provided | 2018-04-23 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000003241 | SCV000941899 | pathogenic | Methylmalonic aciduria, cblB type | 2024-01-28 | 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). 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. |
Myriad Genetics, |
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, |
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). | |
Ai |
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, |
RCV000003241 | SCV002806050 | pathogenic | Methylmalonic aciduria, cblB type | 2022-05-06 | 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. |
Prevention |
RCV003398428 | SCV004104087 | pathogenic | MMAB-related condition | 2023-08-28 | criteria provided, single submitter | 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 (http://gnomad.broadinstitute.org/variant/12-109998873-G-A). In summary, we classify the c.556C>T (p.Arg186Trp) variant as pathogenic. |
Baylor Genetics | RCV000003241 | SCV004193140 | pathogenic | Methylmalonic aciduria, cblB type | 2023-10-03 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000003241 | SCV000023399 | pathogenic | Methylmalonic aciduria, cblB type | 2002-12-15 | no assertion criteria provided | literature only | |
Gene |
RCV000003241 | SCV000258526 | not provided | Methylmalonic aciduria, cblB type | no assertion provided | literature only | ||
Institute of Medical Genetics and Genomics, |
RCV000003241 | SCV000267127 | pathogenic | Methylmalonic aciduria, cblB type | 2014-06-15 | no assertion criteria provided | research | |
Natera, |
RCV000003241 | SCV001459239 | pathogenic | Methylmalonic aciduria, cblB type | 2020-09-16 | no assertion criteria provided | clinical testing | |
Baumgartner lab, |
RCV000003241 | SCV001738795 | pathogenic | Methylmalonic aciduria, cblB type | 2021-06-01 | no assertion criteria provided | clinical testing |