ClinVar Miner

Submissions for variant NM_020166.5(MCCC1):c.974T>G (p.Met325Arg)

gnomAD frequency: 0.00006  dbSNP: rs119103212
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000081995 SCV000225049 pathogenic not provided 2017-01-20 criteria provided, single submitter clinical testing
GeneDx RCV000081995 SCV000239918 pathogenic not provided 2024-01-18 criteria provided, single submitter clinical testing 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)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000081995 SCV000610255 pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000002006 SCV000656964 pathogenic 3-methylcrotonyl-CoA carboxylase 1 deficiency 2024-01-31 criteria provided, single submitter clinical testing 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000614611 SCV000713490 likely pathogenic Methylcrotonyl-CoA carboxylase deficiency 2017-09-07 criteria provided, single submitter clinical testing 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.
SIB Swiss Institute of Bioinformatics RCV000002006 SCV000883183 likely pathogenic 3-methylcrotonyl-CoA carboxylase 1 deficiency 2018-10-15 criteria provided, single submitter curation 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).
Fulgent Genetics, Fulgent Genetics RCV000002006 SCV000894306 likely pathogenic 3-methylcrotonyl-CoA carboxylase 1 deficiency 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000002006 SCV004194264 pathogenic 3-methylcrotonyl-CoA carboxylase 1 deficiency 2024-03-07 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000002006 SCV005044014 likely pathogenic 3-methylcrotonyl-CoA carboxylase 1 deficiency 2024-02-15 criteria provided, single submitter clinical testing PS3, PM2, PM3, PP3
OMIM RCV000002006 SCV000022164 pathogenic 3-methylcrotonyl-CoA carboxylase 1 deficiency 2001-02-01 no assertion criteria provided literature only
Natera, Inc. RCV000002006 SCV002079105 pathogenic 3-methylcrotonyl-CoA carboxylase 1 deficiency 2020-07-17 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.