VCV001521022.11 - ClinVar

NM_022132.5(MCCC2):c.691A>T (p.Ile231Phe)

Germline

Classification

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

Likely pathogenic
Likely pathogenic (3)

3 out of 3 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.691A>T (p.Ile231Phe)

Variation ID: 1521022 Accession: VCV001521022.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q13.2 5: 71626706 (GRCh38) [ NCBI UCSC ] 5: 70922533 (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	Mar 28, 2022	Apr 4, 2026	Mar 26, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_022132.5:c.691A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_071415.1:p.Ile231Phe	missense
NM_001363147.1:c.625-5415A>T		intron variant
NM_022132.4:c.691A>T
NC_000005.10:g.71626706A>T
NC_000005.9:g.70922533A>T
NG_008882.1:g.44419A>T

... more HGVS ... less HGVS

Protein change

I231F

Other names

Canonical SPDI

NC_000005.10:71626705:A: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.

0.00020 (T)

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

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

1000 Genomes Project 0.00020

1000 Genomes Project 30x 0.00031

Links

ClinGen: CA3297842 dbSNP: rs531567604 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	939	953

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	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 26, 2025	RCV002031053.11

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 (Jan 29, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	3-methylcrotonyl-CoA carboxylase 2 deficiency	Baylor Genetics Accession: SCV004194320.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Mar 12, 2024) 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: SCV002313893.5 First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026	Publications: PubMed (2) PubMed: 26589311‚ 29767664 Comment: show This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 231 of the MCCC2 protein (p.Ile231Phe). This variant is present in population databases (rs531567604, gnomAD 0.003%). This missense change has been observed in individual(s) with 3-Methylcrotonylglycinuria (PMID: 26589311, 29767664). 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: 1521022). 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 MCCC2 protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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

Likely pathogenic (Mar 26, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	3-methylcrotonyl-CoA carboxylase 2 deficiency	Natera, Inc. Accession: SCV007522861.1 First in ClinVar: Apr 04, 2026 Last updated: Apr 04, 2026	Publications: PubMed (2) PubMed: 26589311‚ 29767664 Comment: show The c.691A>T variant in MCCC2 is a missense variant predicted to cause substitution of isoleucine to phenylalanine at amino acid 231. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 29767664, 26589311). This variant has been identified in one or more affected individuals with a phenotype highly consistent with the associated gene (PMID: 29767664). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is 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

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 231 of the MCCC2 protein (p.Ile231Phe). This variant is present in population databases (rs531567604, gnomAD 0.003%). This missense change has been observed in individual(s) with 3-Methylcrotonylglycinuria (PMID: 26589311, 29767664). 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: 1521022). 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 MCCC2 protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

The c.691A>T variant in MCCC2 is a missense variant predicted to cause substitution of isoleucine to phenylalanine at amino acid 231. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 29767664, 26589311). This variant has been identified in one or more affected individuals with a phenotype highly consistent with the associated gene (PMID: 29767664). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Likely Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Biochemical and molecular characterization of 3-Methylcrotonylglycinuria in an Italian asymptomatic girl.	Cozzolino C	Genetics and molecular biology	2018	PMID: 29767664
Inborn Errors of Metabolism in the United Arab Emirates: Disorders Detected by Newborn Screening (2011-2014).	Al-Jasmi FA	JIMD reports	2016	PMID: 26589311

Text-mined citations for rs531567604 ...

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