rs119103212
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_020166.5(MCCC1):āc.974T>Gā(p.Met325Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000991 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: š 0.000053 ( 0 hom., cov: 32)
Exomes š: 0.00010 ( 0 hom. )
Consequence
MCCC1
NM_020166.5 missense
NM_020166.5 missense
Scores
10
7
2
Clinical Significance
Conservation
PhyloP100: 8.94
Genes affected
MCCC1 (HGNC:6936): (methylcrotonyl-CoA carboxylase subunit 1) This gene encodes the large subunit of 3-methylcrotonyl-CoA carboxylase. This enzyme functions as a heterodimer and catalyzes the carboxylation of 3-methylcrotonyl-CoA to form 3-methylglutaconyl-CoA. Mutations in this gene are associated with 3-Methylcrotonylglycinuria, an autosomal recessive disorder of leucine catabolism. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
?
In a domain ATP-grasp (size 197) in uniprot entity MCCA_HUMAN there are 17 pathogenic changes around while only 2 benign (89%) in NM_020166.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.929
PP5
?
Variant 3-183045522-A-C is Pathogenic according to our data. Variant chr3-183045522-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MCCC1 | NM_020166.5 | c.974T>G | p.Met325Arg | missense_variant | 10/19 | ENST00000265594.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MCCC1 | ENST00000265594.9 | c.974T>G | p.Met325Arg | missense_variant | 10/19 | 1 | NM_020166.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152220Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251384Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135860
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GnomAD4 exome AF: 0.000104 AC: 152AN: 1461778Hom.: 0 Cov.: 31 AF XY: 0.000102 AC XY: 74AN XY: 727186
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74378
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
3-methylcrotonyl-CoA carboxylase 1 deficiency Pathogenic:7
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Oct 15, 2018 | 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). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2001 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Feb 15, 2024 | PS3, PM2, PM3, PP3 - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 17, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 07, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | 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. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2023 | Published functional studies demonstrate reduced enzymatic activity (Desviat et al., 2003); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25087612, 30609409, 14680978, 11170888, 22642865, 25356967) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 20, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Aug 31, 2017 | - - |
Methylcrotonyl-CoA carboxylase deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 07, 2017 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.;.;.
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;.;D
REVEL
Pathogenic
Sift
Uncertain
D;D;.;.;D
Sift4G
Uncertain
D;D;D;D;.
Polyphen
D;D;.;.;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 18
Find out detailed SpliceAI scores and Pangolin per-transcript scores at