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.
ClinVar Genomic variation as it relates to human health
NM_020166.5(MCCC1):c.974T>G (p.Met325Arg)
Germline
Classification
Help
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.
(11)
Help
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.
Pathogenic/Likely pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_020166.5(MCCC1):c.974T>G (p.Met325Arg)
Variation ID: 1929 Accession: VCV000001929.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3q27.1 3: 183045522 (GRCh38) [ NCBI UCSC ] 3: 182763310 (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 Feb 13, 2015 Sep 16, 2024 Mar 7, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020166.5:c.974T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_064551.3:p.Met325Arg missense NM_001293273.2:c.623T>G NP_001280202.1:p.Met208Arg missense NM_001363880.1:c.647T>G NP_001350809.1:p.Met216Arg missense NR_120639.2:n.797T>G non-coding transcript variant NR_120640.2:n.1641T>G non-coding transcript variant NC_000003.12:g.183045522A>C NC_000003.11:g.182763310A>C NG_008100.1:g.59056T>G Q96RQ3:p.Met325Arg - Protein change
- M325R, M208R, M216R
- Other names
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p.M325R:ATG>AGG
- Canonical SPDI
- NC_000003.12:183045521:A:C
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00007
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| MCCC1 | - | - |
GRCh38 GRCh37 |
838 | 890 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 7, 2024 | RCV000002006.28 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 18, 2024 | RCV000081995.24 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 7, 2017 | RCV000614611.12 |
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. |
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Pathogenic
(Aug 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610255.1
First in ClinVar: Jul 26, 2015 Last updated: Jul 26, 2015 |
|
|
|
Likely pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
3-methylcrotonyl-CoA carboxylase 1 deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894306.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Jan 20, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000225049.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 9
Sex: mixed
|
|
|
Likely pathogenic
(Sep 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Methylcrotonyl-CoA carboxylase deficiency
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000713490.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
|
|
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Likely pathogenic
(Oct 15, 2018)
|
criteria provided, single submitter
Method: curation
|
3-methylcrotonyl-CoA carboxylase 1 deficiency
Affected status: unknown
Allele origin:
germline
|
SIB Swiss Institute of Bioinformatics
Accession: SCV000883183.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Comment:
This variant is interpreted as Likely Pathogenic, for 3-Methylcrotonyl-CoA carboxylase 1 deficiency, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls … (more)
This variant is interpreted as Likely Pathogenic, for 3-Methylcrotonyl-CoA carboxylase 1 deficiency, autosomal recessive. 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. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/11170888). (less)
|
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
3-methylcrotonyl-CoA carboxylase 1 deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000656964.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 325 of the MCCC1 protein (p.Met325Arg). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 325 of the MCCC1 protein (p.Met325Arg). This variant is present in population databases (rs119103212, gnomAD 0.008%). This missense change has been observed in individuals with 3 methylcrotonyl-CoA carboxylase deficiency (PMID: 11170888, 25356967; Invitae). ClinVar contains an entry for this variant (Variation ID: 1929). 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 80%. Experimental studies have shown that this missense change affects MCCC1 function (PMID: 14680978). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Likely pathogenic
(Feb 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
3-methylcrotonyl-CoA carboxylase 1 deficiency
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV005044014.1
First in ClinVar: May 19, 2024 Last updated: May 19, 2024 |
Comment:
PS3, PM2, PM3, PP3
|
|
|
Pathogenic
(Mar 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
3-methylcrotonyl-CoA carboxylase 1 deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004194264.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Jan 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000239918.13
First in ClinVar: Jul 26, 2015 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate reduced enzymatic activity (PMID: 14680978); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not … (more)
Published functional studies demonstrate reduced enzymatic activity (PMID: 14680978); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25087612, 30609409, 22642865, 25356967, 11170888, 14680978) (less)
|
|
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Pathogenic
(Jul 17, 2020)
|
no assertion criteria provided
Method: clinical testing
|
3-methylcrotonyl-CoA carboxylase 1 deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002079105.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Pathogenic
(Feb 01, 2001)
|
no assertion criteria provided
Method: literature only
|
3-@METHYLCROTONYL-CoA CARBOXYLASE 1 DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022164.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 13, 2015 |
Comment on evidence:
In a patient with 3-methylcrotonyl-CoA carboxylase-1 deficiency (MCC1D; 210200), Gallardo et al. (2001) identified a 974T-G transversion in the MCCA gene, resulting in a met325-to-arg … (more)
In a patient with 3-methylcrotonyl-CoA carboxylase-1 deficiency (MCC1D; 210200), Gallardo et al. (2001) identified a 974T-G transversion in the MCCA gene, resulting in a met325-to-arg (M325R) missense mutation. This nonconservative substitution led to absence of labeling of MCC-alpha by biotin, indicating that the mutation affects either the stability or the biotinylation of the protein. (less)
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Comment:
Comment:
This variant is interpreted as Likely Pathogenic, for 3-Methylcrotonyl-CoA carboxylase 1 deficiency, autosomal recessive. 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. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/11170888).
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 325 of the MCCC1 protein (p.Met325Arg). This variant is present in population databases (rs119103212, gnomAD 0.008%). This missense change has been observed in individuals with 3 methylcrotonyl-CoA carboxylase deficiency (PMID: 11170888, 25356967; Invitae). ClinVar contains an entry for this variant (Variation ID: 1929). 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 80%. Experimental studies have shown that this missense change affects MCCC1 function (PMID: 14680978). For these reasons, this variant has been classified as Pathogenic.
Comment:
PS3, PM2, PM3, PP3
Comment:
Published functional studies demonstrate reduced enzymatic activity (PMID: 14680978); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25087612, 30609409, 22642865, 25356967, 11170888, 14680978)
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:
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.
Comment:
This variant is interpreted as Likely Pathogenic, for 3-Methylcrotonyl-CoA carboxylase 1 deficiency, autosomal recessive. 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. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/11170888).
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 325 of the MCCC1 protein (p.Met325Arg). This variant is present in population databases (rs119103212, gnomAD 0.008%). This missense change has been observed in individuals with 3 methylcrotonyl-CoA carboxylase deficiency (PMID: 11170888, 25356967; Invitae). ClinVar contains an entry for this variant (Variation ID: 1929). 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 80%. Experimental studies have shown that this missense change affects MCCC1 function (PMID: 14680978). For these reasons, this variant has been classified as Pathogenic.
Comment:
PS3, PM2, PM3, PP3
Comment:
Published functional studies demonstrate reduced enzymatic activity (PMID: 14680978); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25087612, 30609409, 22642865, 25356967, 11170888, 14680978)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Functional analysis of MCCA and MCCB mutations causing methylcrotonylglycinuria. | Desviat LR | Molecular genetics and metabolism | 2003 | PMID: 14680978 |
| The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism. | Gallardo ME | American journal of human genetics | 2001 | PMID: 11170888 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MCCC1 | - | - | - | - |
Text-mined citations for rs119103212 ...
HelpThese 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 Nov 25, 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.