Segmental overgrowth disorders - Deep sequencing

Gene: AKT2

Green List (high evidence)

The rating of this gene has been updated togreenfollowing NHS Genomic Medicine Service approval.

Created: 4 Dec 2024, 5:08 p.m. | Last Modified: 4 Dec 2024, 5:08 p.m.

Panel Version: 3.19

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Comment on list classification: At least three unrelated families reported with the same activating mosaic c.49G>A (p.E17K) variant in the AKT2 gene. Mild asymmetric overgrowth was seen in 2/3 cases. Sibs from the third family showed early overgrowth but no signs of body asymmetry. Overall the evidence is borderline amber/green. However, as this gene has been expert reviewed as green by Tom Cullup (GOSH) and is likely to be diagnostically relevant, recommending AKT2 is promoted to green status at the next GMS panel update.

Created: 9 Aug 2023, 10:50 a.m. | Last Modified: 9 Aug 2023, 10:50 a.m.

Panel Version: 3.12

Green List (high evidence)

Hot-spot variant Glu17Lys reported multiple times de novo, at least twice mosaic (21979934; 24285683)

Created: 3 May 2023, 3:46 p.m. | Last Modified: 3 May 2023, 3:46 p.m.

Panel Version: 3.5

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
hypoinsulinemic hypoglycemia with hemihypertrophy (HIHGHH) (MIM 240900)

Publications

• 21979934
• 24285683

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Comment on list classification: After consultation with Genomics England clinical team who identified AKT2 in the review paper PMID:28502730 – "4 cases summarised, they all have the same missense variant, and I can’t see if any work has been done re mechanism e.g. gain of function". Advised rating as Amber.

Created: 11 Dec 2019, 11:04 a.m. | Last Modified: 11 Dec 2019, 11:04 a.m.

Panel Version: 1.9