ClinVar Genomic variation as it relates to human health
NM_022132.5(MCCC2):c.599T>A (p.Ile200Asn)
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.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(8); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_022132.5(MCCC2):c.599T>A (p.Ile200Asn)
Variation ID: 167278 Accession: VCV000167278.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q13.2 5: 71604443 (GRCh38) [ NCBI UCSC ] 5: 70900270 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 8, 2016 Apr 15, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_022132.5:c.599T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071415.1:p.Ile200Asn missense NM_001363147.1:c.599T>A NP_001350076.1:p.Ile200Asn missense NC_000005.10:g.71604443T>A NC_000005.9:g.70900270T>A NG_008882.1:g.22156T>A Q9HCC0:p.Ile200Asn - Protein change
- I200N
- Other names
- NM_022132.4(MCCC2):c.599T>A(p.Ile200Asn)
- Canonical SPDI
- NC_000005.10:71604442:T:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00100 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00094
The Genome Aggregation Database (gnomAD) 0.00262
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00292
Exome Aggregation Consortium (ExAC) 0.00197
The Genome Aggregation Database (gnomAD), exomes 0.00210
1000 Genomes Project 0.00100
Trans-Omics for Precision Medicine (TOPMed) 0.00238
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 | ||
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HI score
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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. |
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MCCC2 | - | - |
GRCh38 GRCh38 GRCh38 GRCh38 GRCh37 |
763 | 775 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Dec 1, 2023 | RCV000153473.29 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Jan 28, 2024 | RCV000509529.29 | |
Likely benign (1) |
no assertion criteria provided
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Jan 10, 2020 | RCV001271684.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 10, 2022 | RCV001844053.9 |
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
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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. |
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Uncertain Significance
(Oct 09, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281642.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
Comment:
Converted during submission to Uncertain significance.
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Uncertain significance
(May 31, 2018)
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criteria provided, single submitter
Method: curation
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3-methylcrotonyl-CoA carboxylase 2 deficiency
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000803540.1
First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017 |
Comment:
This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for MCC2D, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => … (more)
This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for MCC2D, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:27601257). (less)
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Uncertain significance
(Feb 25, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000202980.7
First in ClinVar: Feb 02, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 8
Sex: mixed
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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3-methylcrotonyl-CoA carboxylase 2 deficiency
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001315496.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Feb 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002103968.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: MCCC2 c.599T>A (p.Ile200Asn) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of the encoded protein … (more)
Variant summary: MCCC2 c.599T>A (p.Ile200Asn) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, N-terminal domain (IPR011762) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251438 control chromosomes, predominantly at a frequency of 0.0038 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. This frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in MCCC2 causing Methylcrotonyl-CoA Carboxylase Deficiency (0.0038 vs 0.0042), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. Nevertheless, c.599T>A has been reported in the literature in mothers who were identified with an elevated C5OH acylcarnitine level through their infant's newborn screening. These mothers were compound heterozygous with pathogenic variants but remained clinically asymptomatic (Grunert_2012, Shepard_2015, Fonseca_2016). These reports do not provide unequivocal conclusions about association of the variant with Methylcrotonyl-CoA Carboxylase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as likely benign and five ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jan 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329414.7
First in ClinVar: Dec 06, 2016 Last updated: Feb 07, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27601257, 34426522, 22642865, … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27601257, 34426522, 22642865, 25356967) (less)
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Uncertain significance
(Mar 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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3-methylcrotonyl-CoA carboxylase 2 deficiency
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041103.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Likely benign
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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3-methylcrotonyl-CoA carboxylase 2 deficiency
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000765712.7
First in ClinVar: Oct 16, 2017 Last updated: Feb 20, 2024 |
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Uncertain significance
(Oct 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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3-methylcrotonyl-CoA carboxylase 2 deficiency
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884097.3
First in ClinVar: Dec 15, 2018 Last updated: Feb 20, 2024 |
Comment:
The MCCC2 c.599T>A; p.Ile200Asn variant (rs140806722) has been reported in two asymptomatic individuals who also harbored a frameshift variant in the other MCCC2 allele; clinical … (more)
The MCCC2 c.599T>A; p.Ile200Asn variant (rs140806722) has been reported in two asymptomatic individuals who also harbored a frameshift variant in the other MCCC2 allele; clinical information was not provided for one of these individuals, but the other had elevated 3-hydroxyisovaleric acid and 3-hydroxyisovalerylcarnitine (Grünert 2012 and Shepard 2015). The variant is reported as a variant of uncertain significance by multiple laboratories in ClinVar (Variant ID: 167278), and is found in the non-Finnish European population with an overall allele frequency of 0.39% (495/126,690 alleles, including 2 homozygotes) in the Genome Aggregation Database. The isoleucine at codon 200 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen2: benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Ile200Asn variant is uncertain at this time. (less)
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Likely benign
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004162921.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
MCCC2: BS2
Number of individuals with the variant: 3
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Likely benign
(Jan 10, 2020)
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no assertion criteria provided
Method: clinical testing
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3-methylcrotonylglycinuria
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001452999.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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3-methylcrotonyl-CoA carboxylase 2 deficiency
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000607235.1
First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Premature birth (present) , Abnormal delivery (present) , Hypermetropia (present) , Vertigo (present) , Pectus carinatum (present) , Hip dysplasia (present) , Joint hypermobility (present) … (more)
Premature birth (present) , Abnormal delivery (present) , Hypermetropia (present) , Vertigo (present) , Pectus carinatum (present) , Hip dysplasia (present) , Joint hypermobility (present) , Abnormality of the curvature of the vertebral column (present) , Gastrointestinal dysmotility (present) , Abnormality of the stomach (present) , Abnormality of the bladder (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-01-04
Testing laboratory interpretation: Uncertain significance
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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3-Methylcrotonyl-CoA carboxylase deficiency: Mutational spectrum derived from comprehensive newborn screening. | Fonseca H | Gene | 2016 | PMID: 27601257 |
Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD. | Shepard PJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25356967 |
3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals. | Grünert SC | Orphanet journal of rare diseases | 2012 | PMID: 22642865 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MCCC2 | - | - | - | - |
Text-mined citations for rs140806722 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.