ClinVar Miner

Submissions for variant NM_022132.5(MCCC2):c.652G>A (p.Ala218Thr)

dbSNP: rs886043524
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000376860 SCV000340533 likely pathogenic not provided 2016-05-27 criteria provided, single submitter clinical testing
GeneDx RCV000376860 SCV001817783 likely pathogenic not provided 2022-07-18 criteria provided, single submitter clinical testing Identified in the presence of a second variant in an asymptomatic newborn from a cohort of individuals with positive newborn screen for 3-MCC deficiency (Fonseca et al., 2016); 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: 11170888, 26566957, 22642865, 27601257)
Fulgent Genetics, Fulgent Genetics RCV001833370 SCV002808146 likely pathogenic 3-methylcrotonyl-CoA carboxylase 2 deficiency 2022-02-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001833370 SCV003525794 pathogenic 3-methylcrotonyl-CoA carboxylase 2 deficiency 2024-03-03 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 218 of the MCCC2 protein (p.Ala218Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with 3-methylcrotonylglycinuria (PMID: 11170888). ClinVar contains an entry for this variant (Variation ID: 286932). 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 MCCC2 protein function with a positive predictive value of 80%. This variant disrupts the p.Ala218 amino acid residue in MCCC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22264772; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001833370 SCV004194377 likely pathogenic 3-methylcrotonyl-CoA carboxylase 2 deficiency 2023-12-19 criteria provided, single submitter clinical testing
Natera, Inc. RCV001833370 SCV002084293 likely pathogenic 3-methylcrotonyl-CoA carboxylase 2 deficiency 2021-10-06 no assertion criteria provided clinical testing

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