ClinVar

Description

The p.D252G pathogenic mutation (also known as c.755A>G), located in coding exon 7 of the PTEN gene, results from an A to G substitution at nucleotide position 755. The aspartic acid at codon 252 is replaced by glycine, an amino acid with similar properties. This mutation was identified in a child with developmental delay and extreme macrocephaly (Butler MG et al. J Med Genet, 2005 Apr;42:318-21) and was found to be de novo in an individual with oral papillomas, facial papules, and extreme macrocephaly (personal communication, Bubien V et al. J Med Genet, 2013 Apr;50:255-63). In one study, D252G demonstrated greater than a 50% reduction in lipid phosphatase activity compared to wild type PTEN (Wong CW et al. FEBS J, 2020 11;287:4848-4861). This variant demonstrated low intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 06;50:874-882). Other assays also support reduced protein expression and/or functional activity compared to wild type (He X et al. Mol Autism, 2015 Nov;6:63; Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955; Mingo J et al. Eur J Hum Genet, 2018 08;26:1180-1187; Post KL et al. Nat Commun, 2020 04;11:2073). Based on structural analysis, this p.D252G is deleterious (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.