NM_022132.5(MCCC2):c.1065A>T (p.Leu355Phe) AND 3-methylcrotonyl-CoA carboxylase 2 deficiency

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jan 21, 2026
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:: RCV000525215.25

Allele description [Variation Report for NM_022132.5(MCCC2):c.1065A>T (p.Leu355Phe)]

NM_022132.5(MCCC2):c.1065A>T (p.Leu355Phe)

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.1065A>T (p.Leu355Phe)

Other names:

p.L355F:TTA>TTT

HGVS:

NC_000005.10:g.71641068A>T
NG_008882.1:g.58781A>T
NM_001363147.1:c.951A>T
NM_022132.5:c.1065A>TMANE SELECT
NP_001350076.1:p.Leu317Phe
NP_071415.1:p.Leu355Phe
NC_000005.9:g.70936895A>T
NM_022132.4:c.1065A>T
Q9HCC0:p.Leu355Phe

Protein change:

L317F

Links:

UniProtKB: Q9HCC0#VAR_072528; dbSNP: rs757052602

Molecular consequence:

NM_001363147.1:c.951A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_022132.5:c.1065A>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000644141	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 21, 2026)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21071250, 25356967, 28492532
SCV001452530	Natera, Inc.	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Likely pathogenic (Sep 15, 2025)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25356967, 21071250, 27033733 Citation Link,
SCV002022767	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 25, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004194327	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005666613	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 24, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005873958	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 16, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD.

Shepard PJ, Barshop BA, Baumgartner MR, Hansen JB, Jepsen K, Smith EN, Frazer KA.

Genet Med. 2015 Aug;17(8):660-7. doi: 10.1038/gim.2014.157. Epub 2014 Nov 6.

PubMed [citation]

PMID:: 25356967
PMCID:: PMC4422778

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000644141.12

#	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 leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 355 of the MCCC2 protein (p.Leu355Phe). This variant is present in population databases (rs757052602, gnomAD 0.3%). This missense change has been observed in individual(s) with 3-methylcrotonylglycinuria (PMID: 21071250, 25356967; internal data). ClinVar contains an entry for this variant (Variation ID: 203806). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MCCC2 protein function with a positive predictive value of 80%. 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 Natera, Inc., SCV001452530.2

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

Description

The c.1065A>T variant in MCCC2 is a missense variant predicted to cause substitution of leucine to phenylalanine at amino acid 355. 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: 25356967, 21071250, 27033733). This variant has been identified in one or more affected individual with a phenotype highly consistent with the associated gene (PMID: 21071250). 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

From Revvity Omics, Revvity, SCV002022767.4

#	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, SCV004194327.2

#	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 Fulgent Genetics, Fulgent Genetics, SCV005666613.1

#	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

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV005873958.1

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

Description

PS3_Moderate, PM3_Strong

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 4, 2026

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