NM_172250.3(MMAA):c.650T>A (p.Leu217Ter) AND Methylmalonic aciduria, cblA type

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Sep 29, 2022
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:: RCV000203334.14

Allele description [Variation Report for NM_172250.3(MMAA):c.650T>A (p.Leu217Ter)]

NM_172250.3(MMAA):c.650T>A (p.Leu217Ter)

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.650T>A (p.Leu217Ter)

HGVS:

NC_000004.12:g.145646073T>A
NG_007536.2:g.52032T>A
NM_172250.3:c.650T>AMANE SELECT
NP_758454.1:p.Leu217Ter
NP_758454.1:p.Leu217Ter
LRG_1301t1:c.650T>A
LRG_1301:g.52032T>A
LRG_1301p1:p.Leu217Ter
NC_000004.11:g.146567225T>A
NG_007536.1:g.31776T>A
NM_172250.1:c.650T>A
NM_172250.2:c.650T>A

Protein change:

L217*

Links:

dbSNP: rs140356252

NCBI 1000 Genomes Browser:

rs140356252

Molecular consequence:

NM_172250.3:c.650T>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000258478	GeneReviews	no classification provided	not provided	germline	literature only
SCV000799562	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Apr 25, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002240713	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 26, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15308131, 15523652, 15781192, 28492532
SCV004193124	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 29, 2022)	unknown	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Mutations in the MMAA gene in patients with the cblA disorder of vitamin B12 metabolism.

Lerner-Ellis JP, Dobson CM, Wai T, Watkins D, Tirone JC, Leclerc D, Doré C, Lepage P, Gravel RA, Rosenblatt DS.

Hum Mutat. 2004 Dec;24(6):509-16. Erratum in: Hum Mutat. 2005 Mar;25(3):317.

PubMed [citation]

PMID:: 15523652

See all PubMed Citations (5)

Details of each submission

From GeneReviews, SCV000258478.2

#	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 Counsyl, SCV000799562.1

#	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 Invitae, SCV002240713.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 218976). This premature translational stop signal has been observed in individual(s) with methylmalonic acidemia (PMID: 15308131). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu217*) 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).

#	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, SCV004193124.1

#	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

Last Updated: Apr 15, 2024

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