NM_022132.5(MCCC2):c.127C>T (p.Gln43Ter) AND 3-methylcrotonyl-CoA carboxylase 2 deficiency

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Mar 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:: RCV001783635.11

Allele description [Variation Report for NM_022132.5(MCCC2):c.127C>T (p.Gln43Ter)]

NM_022132.5(MCCC2):c.127C>T (p.Gln43Ter)

Gene:

MCCC2:methylcrotonyl-CoA carboxylase subunit 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q13.2

Genomic location:

Preferred name:

NM_022132.5(MCCC2):c.127C>T (p.Gln43Ter)

HGVS:

NC_000005.10:g.71587552C>T
NG_008882.1:g.5265C>T
NM_001363147.1:c.127C>T
NM_022132.5:c.127C>TMANE SELECT
NP_001350076.1:p.Gln43Ter
NP_071415.1:p.Gln43Ter
NC_000005.9:g.70883379C>T

Protein change:

Q43*

Links:

dbSNP: rs2112251855

NCBI 1000 Genomes Browser:

rs2112251855

Molecular consequence:

NM_001363147.1:c.127C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_022132.5:c.127C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: 3-methylcrotonyl-CoA carboxylase 2 deficiency
Synonyms:: METHYLCROTONYLGLYCINURIA, TYPE II; 3 alpha methylcrotonyl-CoA carboxylase 2 deficiency; 3 alpha methylcrotonylglycinuria 2; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008862; MedGen: C1859499; Orphanet: 6; OMIM: 210210

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002017232	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 11, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004194367	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 15, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004293738	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 20, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11181649, 22642865, 16010683, 28492532
SCV004807766	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency.

Baumgartner MR, Almashanu S, Suormala T, Obie C, Cole RN, Packman S, Baumgartner ER, Valle D.

J Clin Invest. 2001 Feb;107(4):495-504.

PubMed [citation]

PMID:: 11181649
PMCID:: PMC199271

3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals.

Grünert SC, Stucki M, Morscher RJ, Suormala T, Bürer C, Burda P, Christensen E, Ficicioglu C, Herwig J, Kölker S, Möslinger D, Pasquini E, Santer R, Schwab KO, Wilcken B, Fowler B, Yue WW, Baumgartner MR.

Orphanet J Rare Dis. 2012 May 29;7:31. doi: 10.1186/1750-1172-7-31.

PubMed [citation]

PMID:: 22642865
PMCID:: PMC3495011

See all PubMed Citations (5)

Details of each submission

From Revvity Omics, Revvity, SCV002017232.3

#	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

From Baylor Genetics, SCV004194367.1

#	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, SCV004293738.2

#	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.Gln43*) in the MCCC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MCCC2 are known to be pathogenic (PMID: 11181649, 22642865). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of MCCC2-related conditions (PMID: 16010683). ClinVar contains an entry for this variant (Variation ID: 1323271). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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 Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre, SCV004807766.1

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

Last Updated: Mar 5, 2025

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