ClinVar Miner

Submissions for variant NM_022132.5(MCCC2):c.478G>A (p.Ala160Thr)

gnomAD frequency: 0.00001  dbSNP: rs727504009
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000153472 SCV000202979 uncertain significance not provided 2014-03-03 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000704177 SCV000833116 uncertain significance 3-methylcrotonyl-CoA carboxylase 2 deficiency 2022-06-02 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 160 of the MCCC2 protein (p.Ala160Thr). This variant is present in population databases (rs727504009, gnomAD 0.003%). This missense change has been observed in individual(s) with unspecified type of inborn error of metabolism (PMID: 32778825). ClinVar contains an entry for this variant (Variation ID: 167277). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc. RCV000704177 SCV001452998 uncertain significance 3-methylcrotonyl-CoA carboxylase 2 deficiency 2020-03-10 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004751297 SCV005346020 uncertain significance MCCC2-related disorder 2024-07-04 no assertion criteria provided clinical testing The MCCC2 c.478G>A variant is predicted to result in the amino acid substitution p.Ala160Thr. This variant was reported in a newborn screening for inborn errors of metabolism; however, clinical information was not provided (Table S5, Adhikari et al. 2020. PubMed ID: 32778825). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. A different missense variant (c.479C>A, Ala160Asp) has been reported, along with another variant of uncertain significance, in a patient with elevated C5-OH by newborn screening suggestive of 3-methylcrotonyl-CoA carboxylase deficiency with mild elevation of 3-methylcrotonylglycine and normal 3-hydroxyisovaleric acid (Cheng et al. 2023. PubMed ID: 36822454). Although we suspect this variant may be pathogenic, at this time, the clinical significance of the c.478G>A variant is uncertain due to the absence of conclusive functional and genetic evidence.

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