NM_022132.5(MCCC2):c.1623G>T (p.Leu541Phe) AND 3-methylcrotonyl-CoA carboxylase 2 deficiency

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 19, 2026
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001881730.8

Allele description [Variation Report for NM_022132.5(MCCC2):c.1623G>T (p.Leu541Phe)]

NM_022132.5(MCCC2):c.1623G>T (p.Leu541Phe)

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.1623G>T (p.Leu541Phe)

HGVS:

NC_000005.10:g.71656791G>T
NG_008882.1:g.74504G>T
NM_001363147.1:c.1509G>T
NM_022132.4:c.1623G>T
NM_022132.5:c.1623G>TMANE SELECT
NP_001350076.1:p.Leu503Phe
NP_071415.1:p.Leu541Phe
NC_000005.9:g.70952618G>T

Protein change:

L503F

Links:

dbSNP: rs753443203

Molecular consequence:

NM_001363147.1:c.1509G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_022132.5:c.1623G>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
SCV002148120	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2026)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32778825, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002148120

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 19, 2026)

germline

clinical testing

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

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

Citations

PubMed

The role of exome sequencing in newborn screening for inborn errors of metabolism.

Adhikari AN, Gallagher RC, Wang Y, Currier RJ, Amatuni G, Bassaganyas L, Chen F, Kundu K, Kvale M, Mooney SD, Nussbaum RL, Randi SS, Sanford J, Shieh JT, Srinivasan R, Sunderam U, Tang H, Vaka D, Zou Y, Koenig BA, Kwok PY, Risch N, et al.

Nat Med. 2020 Sep;26(9):1392-1397. doi: 10.1038/s41591-020-0966-5. Epub 2020 Aug 10.

PubMed [citation]

PMID:: 32778825
PMCID:: PMC8800147

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002148120.5

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 541 of the MCCC2 protein (p.Leu541Phe). This variant is present in population databases (rs753443203, gnomAD 0.006%). This missense change has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 32778825; 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: 1386999). 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

Last Updated: Feb 15, 2026

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