ClinVar Miner

Submissions for variant NM_020166.5(MCCC1):c.863A>G (p.Glu288Gly)

gnomAD frequency: 0.00001  dbSNP: rs746500530
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000549808 SCV000656961 likely pathogenic 3-methylcrotonyl-CoA carboxylase 1 deficiency 2023-11-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 288 of the MCCC1 protein (p.Glu288Gly). This variant is present in population databases (rs746500530, gnomAD 0.04%). This missense change has been observed in individual(s) with 3-methylcrotonyl-CoA carboxylase deficiency (PMID: 22642865, 25382614, 31730530, 31901042). ClinVar contains an entry for this variant (Variation ID: 476400). 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 95%. Experimental studies have shown that this missense change affects MCCC1 function (PMID: 22642865). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002298662 SCV002598928 uncertain significance not specified 2022-09-10 criteria provided, single submitter clinical testing Variant summary: MCCC1 c.863A>G (p.Glu288Gly) results in a non-conservative amino acid change located in the Carbamoyl-phosphate synthetase large subunit-like, ATP-binding domain (IPR005479) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 237242 control chromosomes. c.863A>G has been reported in the literature as a homozygous or presumably compound heterozygous genotype in settings of newborn screening for 3-methylcrotonyl-CoA carboxylase (MCC) deficiency supported by characteristic biochemical findings (example, Grunert_2012, Yang_2015). At-least one of these was reportedly asymptomatic at age 7 with regular follow-up (Grunert_2012), while to our knowledge, the follow-up on the other ascertained individual is unknown (Yang_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Methylcrotonyl-CoA Carboxylase Deficiency, a disorder with a highly variable phenotype ranging from acute neonatal onset with fatal outcome to asymptomatic adults. At least one publication reports experimental evidence evaluating an impact on protein function (Grunert_2012). The most pronounced variant effect results in absence of normal 3-methylcrotonyl-CoA carboxylase (MCC) activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics RCV000549808 SCV004194258 pathogenic 3-methylcrotonyl-CoA carboxylase 1 deficiency 2023-09-19 criteria provided, single submitter clinical testing
Natera, Inc. RCV001275512 SCV001460697 uncertain significance Methylcrotonyl-CoA carboxylase deficiency 2020-09-16 no assertion criteria provided clinical testing

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