VCV001323271.9 - ClinVar

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

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

4 out of 4 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 1323271 Accession: VCV001323271.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q13.2 5: 71587552 (GRCh38) [ NCBI UCSC ] 5: 70883379 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Nov 29, 2021	Feb 23, 2026	Mar 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_022132.5:c.127C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_071415.1:p.Gln43Ter	nonsense
NM_001363147.1:c.127C>T	NP_001350076.1:p.Gln43Ter	nonsense
NC_000005.10:g.71587552C>T
NC_000005.9:g.70883379C>T
NG_008882.1:g.5265C>T

... more HGVS ... less HGVS

Protein change

Q43*

Other names

Canonical SPDI

NC_000005.10:71587551:C:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA360002520 dbSNP: rs2112251855 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MCCC2		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	924	938

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
3-methylcrotonyl-CoA carboxylase 2 deficiency	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 29, 2024	RCV001783635.13

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (May 15, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	3-methylcrotonyl-CoA carboxylase 2 deficiency	Baylor Genetics Accession: SCV004194367.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Mar 29, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	3-methylcrotonyl-CoA carboxylase 2 deficiency	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV004807766.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Aug 11, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	3-methylcrotonyl-CoA carboxylase 2 deficiency	Revvity Omics, Revvity Accession: SCV002017232.4 First in ClinVar: Nov 29, 2021 Last updated: Sep 06, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Mar 20, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	3-methylcrotonyl-CoA carboxylase 2 deficiency	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004293738.3 First in ClinVar: Feb 14, 2024 Last updated: Feb 23, 2026	Publications: PubMed (3) PubMed: 11181649‚ 16010683‚ 22642865 Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals.	Grünert SC	Orphanet journal of rare diseases	2012	PMID: 22642865
3-Methylcrotonyl-CoA carboxylase deficiency: mutation analysis in 28 probands, 9 symptomatic and 19 detected by newborn screening.	Dantas MF	Human mutation	2005	PMID: 16010683
The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency.	Baumgartner MR	The Journal of clinical investigation	2001	PMID: 11181649

Text-mined citations for rs2112251855 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 24, 2026