Submissions for variant NM_022132.5(MCCC2):c.1189C>G (p.Pro397Ala)

dbSNP: rs2112463755

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001971695	SCV002266719	likely pathogenic	3-methylcrotonyl-CoA carboxylase 2 deficiency	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 397 of the MCCC2 protein (p.Pro397Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MCCC2-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1477647). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MCCC2 protein function. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017888	SCV004847445	likely pathogenic	Methylcrotonyl-CoA carboxylase deficiency	2024-02-21	criteria provided, single submitter	clinical testing	The p.Pro397Ala variant in MCCC2 has been reported in the compound heterozygous state with another potentially disease-causing variant in MCCC2 (confirmed in trans) in 1 individual with 3-methylcrotonyl-CoA carboxylase deficiency (3-MCC deficiency) and segregated with disease in 2 affected relatives from 1 family (Invitae pers. comm.). The individual was also confirmed to have 3-MCC deficiency biochemically. The variant was absent from large population studies (gnomAD, v3.1.2). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive 3-methylcrotonyl-CoA carboxylase deficiency. ACMG/AMP Criteria applied: PP1_Moderate, PM3, PM2_Supporting, PP3, PP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699609	SCV005204534	uncertain significance	not specified	2024-06-20	criteria provided, single submitter	clinical testing	Variant summary: MCCC2 c.1189C>G (p.Pro397Ala) 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 was absent in 251330 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1189C>G in individuals affected with Methylcrotonyl-CoA Carboxylase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1477647). Based on the evidence outlined above, the variant was classified as uncertain significance.