NM_052845.4(MMAB):c.700C>T (p.Gln234Ter) AND Methylmalonic aciduria, cblB type

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Mar 6, 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:: RCV000190603.25

Allele description [Variation Report for NM_052845.4(MMAB):c.700C>T (p.Gln234Ter)]

NM_052845.4(MMAB):c.700C>T (p.Gln234Ter)

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.700C>T (p.Gln234Ter)

HGVS:

NC_000012.12:g.109557081G>A
NG_007096.1:g.21417C>T
NM_052845.4:c.700C>TMANE SELECT
NP_443077.1:p.Gln234Ter
NP_443077.1:p.Gln234Ter
NC_000012.11:g.109994886G>A
NM_052845.3:c.700C>T
NR_038118.2:n.811C>T

Protein change:

Q234*

Links:

dbSNP: rs369296618

NCBI 1000 Genomes Browser:

rs369296618

Molecular consequence:

NR_038118.2:n.811C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_052845.4:c.700C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Methylmalonic aciduria, cblB type (MACB)
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
SCV000245632	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq	criteria provided, single submitter (LMM Criteria)	Pathogenic (Nov 10, 2014)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16410054, 21604717, 24033266
SCV000258533	GeneReviews	no classification provided	not provided	germline	literature only
SCV000938483	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16410054, 21604717, 28492532
SCV001459235	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001738806	Baumgartner lab, University Children's Hospital Zurich	no assertion criteria provided	Pathogenic (Jun 1, 2021)	germline	clinical testing
SCV004193132	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 6, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005087012	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16410054, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	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

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Loss of allostery and coenzyme B12 delivery by a pathogenic mutation in adenosyltransferase.

Lofgren M, Banerjee R.

Biochemistry. 2011 Jun 28;50(25):5790-8. doi: 10.1021/bi2006306. Epub 2011 Jun 2.

PubMed [citation]

PMID:: 21604717
PMCID:: PMC3119721

See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq, SCV000245632.1

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

Description

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.

#	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		1	not provided	1	not provided

From GeneReviews, SCV000258533.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000938483.6

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

Description

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.

#	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 Natera, Inc., SCV001459235.1

#	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, SCV001738806.1

#	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 Baylor Genetics, SCV004193132.2

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005087012.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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

#	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

Last Updated: Oct 26, 2024

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