ClinVar

Description

The c.422G>A (p.R141H) alteration is located in coding exon 5 of the PMM2 gene. This alteration results from a G to A substitution at nucleotide position 422, causing the arginine (R) at amino acid position 141 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD) database, the PMM2 c.422G>A alteration was observed in 0.4% (891/224,376) of total alleles studied, with a frequency of 0.84% (177/21,196) in the European (Finnish) subpopulation. This missense alteration is the most frequent disease-causing PMM2 alteration and has been reported in several populations (Matthijs, 1997; Schollen, 2000; Vuillaumier-Barrot, 2000; Bohles, 2001; Quelhas, 2007). While the p.R141H alteration has been reported in compound heterozygosity with a second alteration in numerous patients with PMM2-related congenital disorder of glycosylation, no patients homozygous for this alteration have been reported, likely because it is a severe mutation and homozygosity would be lethal early in development (Matthijs, 1999). This amino acid position is highly conserved in available vertebrate species. The p.R141 amino acid is a crucial part of the distal phosphate binding site in the cap domain of α-PMM2, and loss of the positive charge at this location would impair substrate binding (Silvaggi, 2006). Functional analysis demonstrated that the PMM2 protein product harboring the p.R141H alteration has no residual enzymatic activity when expressed in vitro. Further, the p.R141H protein product had a shortened half-life compared to wild type protein, suggesting that the alteration affects protein stability (Vega, 2011). The p.R141H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.