Skeletal dysplasia

Gene: AKT1

Green List (high evidence)

AD - Proteus (but not Cowden) is listed in Overgrowth (tall stature) syndromes with skeletal involvement gp of SD. Two cases with missense variants reported in association with Cowden (Orloff et al 2013). Proteus is associated with mosaicism for a somatic activating mutation E17K (1-50%). ? test sensitive enough ; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
Unknown

Phenotypes
Cowden syndrome 6 615109; Proteus syndrome, somatic 176920

I don't know

Comment on list classification: Keeping red for now. Associated with Proteus syndrome, somatic in OMIM, more consistent with segmental overgrowth, a mosaic disorder

Created: 11 Dec 2019, 5:08 p.m. | Last Modified: 11 Dec 2019, 5:08 p.m.

Panel Version: 1.283

Associated with several phenotypes in OMIM including Proteus syndrome, somatic # 176920. Proteus syndrome features overgrowth of body parts and is associated with mosaicism for a somatic activating mutation in the AKT1 gene.

PMID: 21793738 - Lindhurst et al 2011 - Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G→A, p.Glu17Lys) in the oncogene AKT1. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines.

The Genomics England clinical team do not consider this appropriate for a green rating on the skeletal dysplasia panel.

Created: 20 Nov 2019, 12:40 p.m. | Last Modified: 20 Nov 2019, 12:50 p.m.

Panel Version: 1.219

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: AKT1; Initial rating suggestion: green

Created: 6 Mar 2019, 11:36 a.m.

Comment on list classification: Tier 2 gene for skeletal dysplasia (Ana Beleza). Only two variants publicly reported variants in phenotype 615109 and none in 176920

Created: 8 Jul 2016, 1:52 p.m.

Green List (high evidence)

Tier 2

Created: 15 Jun 2016, 2:01 p.m.

Mode of inheritance
Unknown

Phenotypes
Cowden syndrome 6 615109; Proteus syndrome, somatic 176920

Variants in this GENE are reported as part of current diagnostic practice