rs369296618
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_052845.4(MMAB):c.700C>T(p.Gln234*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,613,778 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00018 ( 0 hom. )
Consequence
MMAB
NM_052845.4 stop_gained
NM_052845.4 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 2.75
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0704 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-109557081-G-A is Pathogenic according to our data. Variant chr12-109557081-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 203820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109557081-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MMAB | NM_052845.4 | c.700C>T | p.Gln234* | stop_gained | 9/9 | ENST00000545712.7 | NP_443077.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MMAB | ENST00000545712.7 | c.700C>T | p.Gln234* | stop_gained | 9/9 | 1 | NM_052845.4 | ENSP00000445920.1 |
Frequencies
GnomAD3 genomes 0.0000328 AC: 5AN: 152208Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251474Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135912
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GnomAD4 exome AF: 0.000179 AC: 261AN: 1461570Hom.: 0 Cov.: 32 AF XY: 0.000176 AC XY: 128AN XY: 727104
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GnomAD4 genome 0.0000328 AC: 5AN: 152208Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74356
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Methylmalonic aciduria, cblB type Pathogenic:6Other:1
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2024 | This sequence change creates a premature translational stop signal (p.Gln234*) in the MMAB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the MMAB protein. This variant is present in population databases (rs369296618, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria (PMID: 16410054). ClinVar contains an entry for this variant (Variation ID: 203820). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MMAB function (PMID: 21604717). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 10, 2014 | The p.Gln234X variant in MMAB has been reported in 4 compound heterozygous and 2 homozygous individuals with methylmalonic aciduria (Lerner-Ellis 2006). This variant has been identified in 0.012% (1/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs369296618). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 234. This alteration occurs within the last exon and is therefore more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro functional studies provide some evidence that the p.Gln234X variant may impact protein function (Lofgren 2011); however, in vitro assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, the p.Gln234X variant is likely pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Baumgartner lab, University Children's Hospital Zurich | Jun 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | 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) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 13 heterozygotes, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (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 a milder phenotype and later onset (GeneReviews). (SP) 1206 - This variant has been shown to be paternally inherited. Father was tested by Fulgent laboratory. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 06, 2024 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Oct 10, 2016 | - - |
Methylmalonic acidemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 17, 2018 | Variant summary: MMAB c.700C>T (p.Gln234X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.2e-05 in 246252 control chromosomes. c.700C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Lerner-Ellis_2006, O'Shea_2012). One publication reports that ibroblasts from patients with this mutation in homozygous or heterozygous form had higher levels of MCM function than most cblB fibroblasts however that was not found to correlated with any reduction in severity of clinical presentation (Lerner-Ellis_2006). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at