ClinVar Miner

Submissions for variant NM_020166.5(MCCC1):c.974T>G (p.Met325Arg) (rs119103212)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000081995 SCV000225049 pathogenic not provided 2017-01-20 criteria provided, single submitter clinical testing
GeneDx RCV000081995 SCV000239918 likely pathogenic not provided 2016-06-22 criteria provided, single submitter clinical testing The M325R missense variant in the MCCC1 gene has been reported previously in association with 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency (Gallardo et al., 2001; Shepard et al., 2015). M325R is a non-conservative amino acid substitution that was shown to affect either the biotinylation or protein stability of the 3-methylcrotonyl-CoA carboxylase enzyme (Gallardo et al., 2001). Therefore, this variant is interpreted to be likely pathogenic.
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
Invitae RCV000002006 SCV000656964 pathogenic 3 Methylcrotonyl-CoA carboxylase 1 deficiency 2020-10-06 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 325 of the MCCC1 protein (p.Met325Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is present in population databases (rs119103212, ExAC 0.003%). This variant has been observed in individual(s) with 3 methylcrotonyl-CoA carboxylase deficiency (PMID: 11170888, 25356967, Invitae). ClinVar contains an entry for this variant (Variation ID: 1929). Experimental studies have shown that this variant affects MCCC1 protein function (PMID: 14680978). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare 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,; 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 (
Fulgent Genetics,Fulgent Genetics RCV000002006 SCV000894306 likely pathogenic 3 Methylcrotonyl-CoA carboxylase 1 deficiency 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000002006 SCV000022164 pathogenic 3 Methylcrotonyl-CoA carboxylase 1 deficiency 2001-02-01 no assertion criteria provided literature only

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