VCV000570791.19 - ClinVar

NM_022132.5(MCCC2):c.1690T>C (p.Ter564Gln)

Germline

Classification

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

Pathogenic/Likely pathogenic

2 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.1690T>C (p.Ter564Gln)

Variation ID: 570791 Accession: VCV000570791.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q13.2 5: 71656858 (GRCh38) [ NCBI UCSC ] 5: 70952685 (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	Oct 10, 2018	Feb 15, 2026	Dec 23, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_022132.5:c.1690T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_071415.1:p.Ter564Gln	stop lost
NM_001363147.1:c.1576T>C	NP_001350076.1:p.Ter526Gln	stop lost
NC_000005.10:g.71656858T>C
NC_000005.9:g.70952685T>C
NG_008882.1:g.74571T>C

... more HGVS ... less HGVS

Protein change

Other names

*564Q
*526Q

Canonical SPDI

NC_000005.10:71656857:T:C

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00006

Links

ClinGen: CA3298242 dbSNP: rs751970792 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	891	903

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 (1)	criteria provided, single submitter	Dec 23, 2025	RCV000691743.21
Methylcrotonyl-CoA carboxylase deficiency	Likely pathogenic (2)	criteria provided, single submitter	Apr 21, 2025	RCV001271415.5
MCCC2-related disorder	Uncertain significance (1)	no assertion criteria provided	Jun 14, 2024	RCV004751665.1

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.
Pathogenic (Dec 23, 2025) 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: SCV000819533.8 First in ClinVar: Oct 10, 2018 Last updated: Feb 15, 2026	Publications: PubMed (3) PubMed: 16010683‚ 22642865‚ 28492532 Comment: show This sequence change disrupts the translational stop signal of the MCCC2 mRNA. It is expected to extend the length of the MCCC2 protein by 3 additional amino acid residues. This variant is present in population databases (rs751970792, gnomAD 0.007%). This protein extension has been observed in individual(s) with 3 Methylcrotonyl-CoA carboxylase deficiency (PMID: 16010683, 22642865; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 570791). 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

Likely pathogenic (Apr 21, 2025) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Methylcrotonyl-CoA carboxylase deficiency	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004029650.2 First in ClinVar: Aug 26, 2023 Last updated: Jun 29, 2025	Publications: PubMed (1) PubMed: 16010683 Comment: show Variant summary: MCCC2 c.1690T>C (p.X564GlnextX3) changes the termination codon and is predicted to lead to an extended protein with three additional amino acids added to the normal C-terminus. MCCC2 c.1690T>C (p.X564GlnextX3) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 2.8e-05 in 251414 control chromosomes. c.1690T>C has been observed in individual(s) affected with pathognomic clinical and metabolic features of Methylcrotonyl-CoA Carboxylase Deficiency (example: Dantas_2005 overlapping with Grunert_2012 and internal data). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16010683, 22642865). ClinVar contains an entry for this variant (Variation ID: 570791). Based on the evidence outlined above, the variant was classified as likely 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

Uncertain significance (Sep 16, 2020) N Not contributing to aggregate classification	no assertion criteria provided	3-methylcrotonylglycinuria	Natera, Inc. Accession: SCV001452541.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jun 14, 2024) N Not contributing to aggregate classification	no assertion criteria provided	MCCC2-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV005360469.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: show The MCCC2 c.1690T>C variant is predicted to result in extension of the open reading frame (p.564Glnext3). This variant is predicted to abolish the stop codon and lead to the extension of the protein by 3 amino acids (p.564Glnext3). This variant has been reported in the heterozygous state in two patients. A second variant was not identified in the MCCC2 gene of either patient, though no RNA was identified from the second allele in one of the patients, suggesting the presence of an additional variant not detectable via the methodology used by the researchers (Dantas et al. 2005. PubMed ID: 16010683; Grünert et al. 2012. PubMed ID: 22642865). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (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 disrupts the translational stop signal of the MCCC2 mRNA. It is expected to extend the length of the MCCC2 protein by 3 additional amino acid residues. This variant is present in population databases (rs751970792, gnomAD 0.007%). This protein extension has been observed in individual(s) with 3 Methylcrotonyl-CoA carboxylase deficiency (PMID: 16010683, 22642865; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 570791). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: MCCC2 c.1690T>C (p.X564GlnextX3) changes the termination codon and is predicted to lead to an extended protein with three additional amino acids added to the normal C-terminus. MCCC2 c.1690T>C (p.X564GlnextX3) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 2.8e-05 in 251414 control chromosomes. c.1690T>C has been observed in individual(s) affected with pathognomic clinical and metabolic features of Methylcrotonyl-CoA Carboxylase Deficiency (example: Dantas_2005 overlapping with Grunert_2012 and internal data). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16010683, 22642865). ClinVar contains an entry for this variant (Variation ID: 570791). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

The MCCC2 c.1690T>C variant is predicted to result in extension of the open reading frame (p.*564Glnext*3). This variant is predicted to abolish the stop codon and lead to the extension of the protein by 3 amino acids (p.*564Glnext*3). This variant has been reported in the heterozygous state in two patients. A second variant was not identified in the MCCC2 gene of either patient, though no RNA was identified from the second allele in one of the patients, suggesting the presence of an additional variant not detectable via the methodology used by the researchers (Dantas et al. 2005. PubMed ID: 16010683; Grünert et al. 2012. PubMed ID: 22642865). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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

Text-mined citations for rs751970792 ...

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 Apr 13, 2026