NM_020166.5(MCCC1):c.974T>G (p.Met325Arg) AND Methylcrotonyl-CoA carboxylase deficiency

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 7, 2017
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:: RCV000614611.12

Allele description [Variation Report for NM_020166.5(MCCC1):c.974T>G (p.Met325Arg)]

NM_020166.5(MCCC1):c.974T>G (p.Met325Arg)

Gene:

MCCC1:methylcrotonyl-CoA carboxylase subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q27.1

Genomic location:

Preferred name:

NM_020166.5(MCCC1):c.974T>G (p.Met325Arg)

Other names:

p.M325R:ATG>AGG

HGVS:

NC_000003.12:g.183045522A>C
NG_008100.1:g.59056T>G
NM_001293273.2:c.623T>G
NM_001363880.1:c.647T>G
NM_020166.5:c.974T>GMANE SELECT
NP_001280202.1:p.Met208Arg
NP_001350809.1:p.Met216Arg
NP_064551.3:p.Met325Arg
NP_064551.3:p.Met325Arg
NP_064551.3:p.Met325Arg
NC_000003.11:g.182763310A>C
NM_020166.3:c.974T>G
NM_020166.4:c.974T>G
NR_120639.2:n.797T>G
NR_120640.2:n.1641T>G
Q96RQ3:p.Met325Arg

Protein change:

M208R; MET325ARG

Links:

UniProtKB: Q96RQ3#VAR_012786; OMIM: 609010.0001; dbSNP: rs119103212

NCBI 1000 Genomes Browser:

rs119103212

Molecular consequence:

NM_001293273.2:c.623T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001363880.1:c.647T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_020166.5:c.974T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_120639.2:n.797T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_120640.2:n.1641T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Methylcrotonyl-CoA carboxylase deficiency
Synonyms:: Deficiency of methylcrotonoyl-CoA carboxylase; 3 Methylcrotonylglycinuria; 3-MCC Deficiency
Identifiers:: MONDO: MONDO:0018950; MedGen: C4551505; OMIM: PS210200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000713490	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Sep 7, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11170888, 25356967, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000713490

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Sep 7, 2017)

germline

clinical testing

PubMed (3)
[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	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism.

Gallardo ME, Desviat LR, Rodríguez JM, Esparza-Gordillo J, Pérez-Cerdá C, Pérez B, Rodríguez-Pombo P, Criado O, Sanz R, Morton DH, Gibson KM, Le TP, Ribes A, de Córdoba SR, Ugarte M, Peñalva MA.

Am J Hum Genet. 2001 Feb;68(2):334-46. Epub 2001 Jan 17.

PubMed [citation]

PMID:: 11170888
PMCID:: PMC1235267

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 (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000713490.1

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

Description

The p.Met325Arg (NM_020166.3 c.974T>G) variant in MCCC1 has been reported in 1 h omozygous and 2 compound heterozygous individuals with 3-methylcrotonyl-CoA carb oxylase deficiency (MCCD type 1), one of whom was an asymptomatic mother who was discovered by newborn screening results of their baby (Gallardo 2001 and Shep ard 2015). This variant has also been reported in ClinVar (Variation ID#1929). F unctional studies support for an impact to the protein (Gallardo 2001). This var iant has been identified in 2/24024 of African chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs119103212). Alt hough this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, althoug h additional studies are required to fully establish its clinical significance, the p.Met325Arg variant is likely pathogenic for MCCD type 1 in an autosomal rec essive manner based upon its biallelic occurrence in individuals with this disea se and low frequency in controls.

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

Last Updated: Nov 30, 2024

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