Submissions for variant NM_022132.5(MCCC2):c.1570G>A (p.Ala524Thr)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002283420	SCV002572024	uncertain significance	not specified	2022-08-14	criteria provided, single submitter	clinical testing	Variant summary: MCCC2 c.1570G>A (p.Ala524Thr) results in a non-conservative amino acid change located in the Acetyl-coenzyme A carboxyltransferase, C-terminal domain (IPR011763) 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 2.4e-05 in 251342 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1570G>A has been reported in the literature as a presumably compound heterozygous (phase not specified) genotype in an asymptomatic newborn as part of the newborn screening program for Methylcrotonyl-CoA Carboxylase Deficiency (example, Fonseca_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Methylcrotonyl-CoA Carboxylase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003096363	SCV003525795	pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2024-10-08	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 524 of the MCCC2 protein (p.Ala524Thr). This variant is present in population databases (rs774241918, gnomAD 0.01%). This missense change has been observed in individual(s) with 3 methylcrotonyl-CoA carboxylase deficiency (PMID: 22658692, 27601257; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1705095). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MCCC2 protein function with a positive predictive value of 80%. This variant disrupts the p.Ala524 amino acid residue in MCCC2. Other variant(s) that disrupt this residue have been observed in individuals with MCCC2-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003096363	SCV003835569	likely pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2024-02-15	criteria provided, single submitter	clinical testing