NM_020166.5(MCCC1):c.1315G>A (p.Val439Met) AND 3-methylcrotonyl-CoA carboxylase 1 deficiency

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Mar 11, 2024
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:: RCV000653496.19

Allele description [Variation Report for NM_020166.5(MCCC1):c.1315G>A (p.Val439Met)]

NM_020166.5(MCCC1):c.1315G>A (p.Val439Met)

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.1315G>A (p.Val439Met)

HGVS:

NC_000003.12:g.183039088C>T
NG_008100.1:g.65490G>A
NM_001293273.2:c.964G>A
NM_001363880.1:c.988G>A
NM_020166.5:c.1315G>AMANE SELECT
NP_001280202.1:p.Val322Met
NP_001350809.1:p.Val330Met
NP_064551.3:p.Val439Met
NP_064551.3:p.Val439Met
NP_064551.3:p.Val439Met
NC_000003.11:g.182756876C>T
NM_020166.3:c.1315G>A
NM_020166.4:c.1315G>A
NR_120639.2:n.1138G>A
NR_120640.2:n.1982G>A
Q96RQ3:p.Val439Met

Protein change:

V322M

Links:

UniProtKB: Q96RQ3#VAR_072504; dbSNP: rs398124352

NCBI 1000 Genomes Browser:

rs398124352

Molecular consequence:

NM_001293273.2:c.964G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001363880.1:c.988G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020166.5:c.1315G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_120639.2:n.1138G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_120640.2:n.1982G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: 3-methylcrotonyl-CoA carboxylase 1 deficiency (MCC1D)
Synonyms:: MCCD TYPE 1; METHYLCROTONYLGLYCINURIA TYPE I; MCC 1 deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008861; MedGen: C0268600; Orphanet: 6; OMIM: 210200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000775376	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22642865, 31901042, 28492532
SCV002079098	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Dec 23, 2020)	germline	clinical testing
SCV004194261	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 11, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000775376

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 25, 2024)

germline

clinical testing

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

SCV002079098

Natera, Inc.

no assertion criteria provided

Likely pathogenic
(Dec 23, 2020)

germline

clinical testing

SCV004194261

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 11, 2024)

unknown

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	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

3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals.

Grünert SC, Stucki M, Morscher RJ, Suormala T, Bürer C, Burda P, Christensen E, Ficicioglu C, Herwig J, Kölker S, Möslinger D, Pasquini E, Santer R, Schwab KO, Wilcken B, Fowler B, Yue WW, Baumgartner MR.

Orphanet J Rare Dis. 2012 May 29;7:31. doi: 10.1186/1750-1172-7-31.

PubMed [citation]

PMID:: 22642865
PMCID:: PMC3495011

[Genetic analysis of newborns with abnormal metabolism of 3-hydroxyisovalerylcarnitine].

Wu D, Lu B, Yang J, Yang R, Huang X, Tong F, Zheng J, Zhao Z.

Zhejiang Da Xue Xue Bao Yi Xue Ban. 2019 Jun 25;48(4):390-396. Chinese.

PubMed [citation]

PMID:: 31901042
PMCID:: PMC8800779

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000775376.6

#	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 valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 439 of the MCCC1 protein (p.Val439Met). This variant is present in population databases (rs398124352, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 22642865, 31901042; Invitae). ClinVar contains an entry for this variant (Variation ID: 95940). 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 expected to disrupt MCCC1 protein function with a positive predictive value of 95%. 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., SCV002079098.1

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

#	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, SCV004194261.2

#	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

Last Updated: Oct 26, 2024

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