NM_052845.4(MMAB):c.14G>A (p.Gly5Asp) AND Methylmalonic aciduria, cblB type

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jun 17, 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:: RCV001277396.4

Allele description [Variation Report for NM_052845.4(MMAB):c.14G>A (p.Gly5Asp)]

NM_052845.4(MMAB):c.14G>A (p.Gly5Asp)

Genes:

MMAB:metabolism of cobalamin associated B [Gene - OMIM - HGNC]
MVK:mevalonate kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.11

Genomic location:

Preferred name:

NM_052845.4(MMAB):c.14G>A (p.Gly5Asp)

HGVS:

NC_000012.12:g.109573467C>T
NG_007096.1:g.5031G>A
NG_007702.1:g.4773C>T
NM_052845.4:c.14G>AMANE SELECT
NP_443077.1:p.Gly5Asp
LRG_156:g.4773C>T
NC_000012.11:g.110011272C>T
NM_052845.3:c.14G>A
NR_038118.2:n.38G>A

Protein change:

G5D

Links:

dbSNP: rs769048646

NCBI 1000 Genomes Browser:

rs769048646

Molecular consequence:

NM_052845.4:c.14G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_038118.2:n.38G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV001464344	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 1, 2020)	germline	clinical testing
SCV002780348	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 19, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003521396	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001464344

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Sep 1, 2020)

germline

clinical testing

SCV002780348

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 19, 2021)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003521396

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 17, 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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Natera, Inc., SCV001464344.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002780348.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003521396.1

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 5 of the MMAB protein (p.Gly5Asp). This variant is present in population databases (rs769048646, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MMAB-related conditions. ClinVar contains an entry for this variant (Variation ID: 989541). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MMAB protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 8, 2024

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