NM_172250.3(MMAA):c.202C>T (p.Gln68Ter) AND Methylmalonic aciduria, cblA type

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 13, 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:: RCV000509034.7

Allele description [Variation Report for NM_172250.3(MMAA):c.202C>T (p.Gln68Ter)]

NM_172250.3(MMAA):c.202C>T (p.Gln68Ter)

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.202C>T (p.Gln68Ter)

HGVS:

NC_000004.12:g.145639341C>T
NG_007536.2:g.45300C>T
NM_172250.3:c.202C>TMANE SELECT
NP_758454.1:p.Gln68Ter
LRG_1301t1:c.202C>T
LRG_1301:g.45300C>T
LRG_1301p1:p.Gln68Ter
NC_000004.11:g.146560493C>T
NG_007536.1:g.25044C>T
NM_172250.2:c.202C>T

Protein change:

Q68*

Links:

dbSNP: rs754894257

NCBI 1000 Genomes Browser:

rs754894257

Molecular consequence:

NM_172250.3:c.202C>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
SCV000606782	University Children's Hospital, University of Zurich	criteria provided, single submitter (ZB-IEM Variant Assertion Criteria)	Pathogenic	germline	clinical testing	Citation Link,
SCV002237523	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 13, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15523652, 15781192, 28497574, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000606782

University Children's Hospital, University of Zurich

criteria provided, single submitter

(ZB-IEM Variant Assertion Criteria)

Pathogenic

germline

clinical testing

Citation Link,

SCV002237523

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 13, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

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

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

See all PubMed Citations (4)

Details of each submission

From University Children's Hospital, University of Zurich, SCV000606782.2

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

From Invitae, SCV002237523.3

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

Description

This sequence change creates a premature translational stop signal (p.Gln68*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with methylmalonic aciduria due to cobalamin A deficiency (PMID: 28497574). ClinVar contains an entry for this variant (Variation ID: 440796). 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

Last Updated: Feb 20, 2024

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