NM_172250.3(MMAA):c.433C>T (p.Arg145Ter) AND Methylmalonic aciduria, cblA type

Germline classification:: Pathogenic/Likely pathogenic (13 submissions)
Last evaluated:: Jan 29, 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:: RCV000003310.36

Allele description [Variation Report for NM_172250.3(MMAA):c.433C>T (p.Arg145Ter)]

NM_172250.3(MMAA):c.433C>T (p.Arg145Ter)

Gene:

MMAA:metabolism of cobalamin associated A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4q31.21

Genomic location:

Preferred name:

NM_172250.3(MMAA):c.433C>T (p.Arg145Ter)

Other names:

rs104893851; p.R145*:CGA>TGA

HGVS:

NC_000004.12:g.145639572C>T
NG_007536.2:g.45531C>T
NM_172250.3:c.433C>TMANE SELECT
NP_758454.1:p.Arg145Ter
NP_758454.1:p.Arg145Ter
LRG_1301t1:c.433C>T
LRG_1301:g.45531C>T
LRG_1301p1:p.Arg145Ter
NC_000004.11:g.146560724C>T
NG_007536.1:g.25275C>T
NM_172250.1:c.433C>T
NM_172250.2:c.433C>T
p.Arg145X

Protein change:

R145*; ARG145TER

Links:

OMIM: 607481.0005; dbSNP: rs104893851

NCBI 1000 Genomes Browser:

rs104893851

Molecular consequence:

NM_172250.3:c.433C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Methylmalonic aciduria, cblA type
Synonyms:: Methylmalonic aciduria, vitamin b12-responsive, due to defect in synthesis of adenosylcobalamin, cbla complementation type; MMA cbl A type; Methylmalonic acidemia cblA type; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009613; MedGen: C1855109; Orphanet: 28; Orphanet: 79310; OMIM: 251100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000023468	OMIM	no assertion criteria provided	Pathogenic (Dec 1, 2004)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000238443	Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq	no assertion criteria provided	Pathogenic (Jan 8, 2015)	germline	research	PubMed (2) [See all records that cite these PMIDs] 15308131, 15523652
SCV000258475	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 15523652, 15781192
SCV000641766	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 15781192, 15308131, 15523652, 16247646, 17957493, 23026888, 26270765, 27591164, 28492532
SCV000882545	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	no assertion criteria provided	Pathogenic (Dec 18, 2018)	germline	clinical testing
SCV001194000	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 20, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001448978	Knight Diagnostic Laboratories, Oregon Health and Sciences University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 21, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001452009	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001522201	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 17, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002075002	GenomeConnect, ClinGen	no classification provided	not provided	paternal	phenotyping only
SCV002499170	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 11, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002810440	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 3, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003821662	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 11, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

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
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	research
not provided	paternal	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only
Hindu/Chauhan	germline	no	1	not provided	not provided	not provided	not provided	clinical testing
Spanish	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants.

Martínez MA, Rincón A, Desviat LR, Merinero B, Ugarte M, Pérez B.

Mol Genet Metab. 2005 Apr;84(4):317-25. Epub 2005 Jan 22.

PubMed [citation]

PMID:: 15781192

Mutation analysis of the MMAA and MMAB genes in Japanese patients with vitamin B(12)-responsive methylmalonic acidemia: identification of a prevalent MMAA mutation.

Yang X, Sakamoto O, Matsubara Y, Kure S, Suzuki Y, Aoki Y, Suzuki Y, Sakura N, Takayanagi M, Iinuma K, Ohura T.

Mol Genet Metab. 2004 Aug;82(4):329-33.

PubMed [citation]

PMID:: 15308131

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000023468.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In the genomic DNA of 37 cblA patients, Lerner-Ellis et al. (2004) identified 18 novel mutations in the MMAA gene, including a 433C-T transition (arg145 to ter; R145X) in exon 2 that represented 43% of pathogenic alleles; a common haplotype was identified.

#	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		not provided	not provided	not provided	not provided

From Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq, SCV000238443.1

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

Description

The heterozygous variant in the MMAA gene (c.433C>T; p.Arg145*) is considered a pathogenic variant. This change represents a rare premature truncation resulting in a product 1/3 of the expected length with the last ~ 273 amino acids being truncated off. This variant has been seen previously by Yang et al (PMID: 15308131) in a one individual in a Japanese affected individuals. In the ExAC dataset this variant was seen on 19 alleles out of 121038 tested, with all tested individuals being heterozygous for the change.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000258475.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Spanish	not provided	not provided	not provided	literature only	PubMed (2)

#	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 Invitae, SCV000641766.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change creates a premature translational stop signal (p.Arg145*) in the MMAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMAA are known to be pathogenic (PMID: 15523652, 15781192). This variant is present in population databases (rs104893851, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria due to cobalamin A deficiency (PMID: 15308131, 15523652, 16247646, 17957493, 23026888, 26270765, 27591164). ClinVar contains an entry for this variant (Variation ID: 3160). 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 Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV000882545.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Hindu/Chauhan	1	not provided	not provided	clinical testing	not provided

Description

The variant NM_172250.3:c.433C>T (p.Arg145Ter) in exon-2 of MMAA gene has been seen in heterozygous status. It is a nonsense variant that results in a stop codon and premature truncation of the protein. This variant has not been reported in the 1000 Genomes database and has a minor allele frequency of 0.02% in the ExAc database. The in-silico prediction of this variant is damaging by MutationTaster2.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001194000.2

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

Description

NM_172250.2(MMAA):c.433C>T(R145*) is classified as pathogenic in the context of methylmalonic acidemia, cblA type. Sources cited for classification include the following: PMID 15523652. Classification of NM_172250.2(MMAA):c.433C>T(R145*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

#	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 Knight Diagnostic Laboratories, Oregon Health and Sciences University, SCV001448978.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Natera, Inc., SCV001452009.1

#	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 Baylor Genetics, SCV001522201.1

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GenomeConnect, ClinGen, SCV002075002.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpreted as Pathogenic and reported on 12-12-2018 by Lab or GTR ID 1006. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	unknown	not provided	not provided	validation		not provided	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002499170.1

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

Description

PVS1, PM3_Strong

#	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 Fulgent Genetics, Fulgent Genetics, SCV002810440.1

#	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 Revvity Omics, Revvity, SCV003821662.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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