NM_022132.5(MCCC2):c.1065A>T (p.Leu355Phe) AND Inborn genetic diseases

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 8, 2025
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:: RCV002513958.4

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:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003717149	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 8, 2025)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21071250, 25356967, 27033733, 38146699 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003717149

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 8, 2025)

germline

clinical testing

PubMed (4)
[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

Citations

PubMed

Novel mutations in the human MCCA and MCCB gene causing methylcrotonylglycinuria.

Nguyen KV, Naviaux RK, Patra S, Barshop BA, Nyhan WL.

Mol Genet Metab. 2011 Feb;102(2):218-21. doi: 10.1016/j.ymgme.2010.10.008. Epub 2010 Oct 20.

PubMed [citation]

PMID:: 21071250

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 (4)

Details of each submission

From Ambry Genetics, SCV003717149.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The c.1065A>T (p.L355F) alteration is located in exon 11 (coding exon 11) of the MCCC2 gene. This alteration results from a A to T substitution at nucleotide position 1065, causing the leucine (L) at amino acid position 355 to be replaced by a phenylalanine (F). Based on data from gnomAD, the T allele has an overall frequency of 0.036% (90/251280) total alleles studied. The highest observed frequency was 0.257% (89/34574) of Latino alleles. This alteration has been detected in the homozygous state and/or in conjunction with other MCCC2 variant(s) in multiple unrelated individuals with 3-methylcrotonyl-CoA carboxylase deficiency (Nguyen, 2011; Forsyth, 2016; Cook, 2024) This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is 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: Apr 4, 2026

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