NM_022132.5(MCCC2):c.691A>T (p.Ile231Phe) AND 3-methylcrotonyl-CoA carboxylase 2 deficiency

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Mar 26, 2025
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:: RCV002031053.11

Allele description [Variation Report for NM_022132.5(MCCC2):c.691A>T (p.Ile231Phe)]

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

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.691A>T (p.Ile231Phe)

HGVS:

NC_000005.10:g.71626706A>T
NG_008882.1:g.44419A>T
NM_001363147.1:c.625-5415A>T
NM_022132.5:c.691A>TMANE SELECT
NP_071415.1:p.Ile231Phe
NC_000005.9:g.70922533A>T
NM_022132.4:c.691A>T

Protein change:

I231F

Links:

dbSNP: rs531567604

Molecular consequence:

NM_001363147.1:c.625-5415A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_022132.5:c.691A>T - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002313893	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 12, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26589311, 29767664, 28492532
SCV004194320	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 29, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV007522861	Natera, Inc.	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Likely pathogenic (Mar 26, 2025)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29767664, 26589311 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002313893

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 12, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004194320

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 29, 2024)

unknown

clinical testing

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

SCV007522861

Natera, Inc.

criteria provided, single submitter

(Natera Variant Classification Schema (03/2026))

Likely pathogenic
(Mar 26, 2025)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

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

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

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

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002313893.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	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, SCV004194320.2

#	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 Natera, Inc., SCV007522861.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	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: Apr 12, 2026

ClinVar

Relating variation to medicine