VCV000001927.15 - ClinVar

NM_022132.5(MCCC2):c.838G>T (p.Asp280Tyr)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

4 out of 5 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_022132.5(MCCC2):c.838G>T (p.Asp280Tyr)

Variation ID: 1927 Accession: VCV000001927.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q13.2 5: 71634977 (GRCh38) [ NCBI UCSC ] 5: 70930804 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 11, 2015	Feb 25, 2025	Apr 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_022132.5:c.838G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_071415.1:p.Asp280Tyr	missense
NM_001363147.1:c.724G>T	NP_001350076.1:p.Asp242Tyr	missense
NC_000005.10:g.71634977G>T
NC_000005.9:g.70930804G>T
NG_008882.1:g.52690G>T
	Q9HCC0:p.Asp280Tyr

... more HGVS ... less HGVS

Protein change

D280Y, D242Y

Other names

Canonical SPDI

NC_000005.10:71634976:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00006

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

UniProtKB: Q9HCC0#VAR_067199 OMIM: 609014.0009 dbSNP: rs119103226 ClinGen: CA251973 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MCCC2		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	824	837

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
3-methylcrotonyl-CoA carboxylase 2 deficiency	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Apr 9, 2024	RCV000002004.18

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 06, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	3-methylcrotonyl-CoA carboxylase 2 deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000955887.7 First in ClinVar: Aug 14, 2019 Last updated: Feb 25, 2025	Publications: PubMed (4) PubMed: 17968484‚ 22030835‚ 22150417‚ 28018443 Comment: This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 280 of the MCCC2 protein … (more) This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 280 of the MCCC2 protein (p.Asp280Tyr). This variant is present in population databases (rs119103226, gnomAD 0.09%). This missense change has been observed in individuals with 3 methylcrotonyl-CoA carboxylase deficiency (PMID: 17968484, 22030835, 22150417, 28018443). ClinVar contains an entry for this variant (Variation ID: 1927). 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 MCCC2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (May 13, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	3-methylcrotonyl-CoA carboxylase 2 deficiency Affected status: yes Allele origin: germline	Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University Accession: SCV001622419.1 First in ClinVar: May 20, 2021 Last updated: May 20, 2021 Comment: The heterozygous variants in MCCC2 gene c.592C>T (p. Gln198*) and c.838G>T (p. Asp280Tyr) were identified in a patient.	Publications: PubMed (1) PubMed: 17968484 Clinical Features: Hearing abnormality (present) , Hypertonia (present) , Myoclonic spasms (present) , EEG abnormality (present) , Seizure (present)
Pathogenic (Feb 29, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	3-methylcrotonyl-CoA carboxylase 2 deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004194350.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (Apr 09, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	3-methylcrotonyl-CoA carboxylase 2 deficiency Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV005666607.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025
Pathogenic (Jan 01, 2007) N Not contributing to aggregate classification	no assertion criteria provided Method: literature only	3-@METHYLCROTONYL-CoA CARBOXYLASE 2 DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022162.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015	Publications: PubMed (1) PubMed: 17968484 Comment on evidence: For discussion of the asp280-to-tyr (D280Y) mutation in the MCCC2 gene that was found in compound heterozygous state in a patient with MCC2 deficiency (MCC2D; … (more) For discussion of the asp280-to-tyr (D280Y) mutation in the MCCC2 gene that was found in compound heterozygous state in a patient with MCC2 deficiency (MCC2D; 210210) by Uematsu et al. (2007), see 609014.0008. (less)

Comment:

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 280 of the MCCC2 protein (p.Asp280Tyr). This variant is present in population databases (rs119103226, gnomAD 0.09%). This missense change has been observed in individuals with 3 methylcrotonyl-CoA carboxylase deficiency (PMID: 17968484, 22030835, 22150417, 28018443). ClinVar contains an entry for this variant (Variation ID: 1927). 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 MCCC2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Maternal 3-methylcrotonyl-coenzyme A carboxylase deficiency with elevated 3-hydroxyisovalerylcarnitine in breast milk.	Cho KL	Korean journal of pediatrics	2016	PMID: 28018443
Mutational spectrum in eight Korean patients with 3-methylcrotonyl-CoA carboxylase deficiency.	Cho SY	Clinical genetics	2012	PMID: 22150417
Uneventful clinical courses of Korean patients with methylcrotonylglycinuria and their common mutations.	Jung CW	Journal of human genetics	2012	PMID: 22030835
Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA carboxylase deficiency.	Uematsu M	Journal of human genetics	2007	PMID: 17968484

Text-mined citations for rs119103226 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 26, 2025

ClinVar Genomic variation as it relates to human health

NM_022132.5(MCCC2):c.838G>T (p.Asp280Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs119103226 ...