ClinVar Genomic variation as it relates to human health

Variant summary: MUT c.1073T>C (p.Leu358Pro) results in a non-conservative amino acid change in Methylmalonyl-CoA mutase, catalytic alpha chain (IPR006098) 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 250930 control chromosomes. c.1073T>C has been reported in the literature in several individuals affected with Methylmalonic Acidemia (example, Brassier_2020, Forny_2023, Horster_2021, Merinero_2008). Particularly, it was reported at a compound heterozygous state with different pathogenic variants in at-least two Methylmalonic Acidemia patients (Horster_2021, Merinero_2008). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31525265, 36717752, 32754920, 17957493). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

For these reasons, this variant has been classified as Pathogenic. 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 MUT protein function. This missense change has been observed in individual(s) with methylmalonic aciduria (PMID: 17957493, 31525265, 32754920). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 358 of the MUT protein (p.Leu358Pro).