Lipodystrophy - childhood onset

Gene: AKT2

I don't know

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. Comment from GMS: 'Should be amber. Another family is needed for AKT2 for this to be upgraded to Green. The two variants used as evidence, p.Arg467Trp and p.Arg208Lys, far too common in gnomAD to be causing a rare AD disorder.'

Created: 3 May 2024, 7:50 p.m. | Last Modified: 3 May 2024, 7:50 p.m.

Panel Version: 4.52

Comment on list classification: Two unrelated cases and supporting functional evidence from mouse models suggest that this gene can be promoted to green rating in the next GMS review.

Created: 2 Aug 2023, 6:16 p.m. | Last Modified: 2 Aug 2023, 6:16 p.m.

Panel Version: 4.9

PMID:15166380 - A missense variant (p.Arg274His) in AKT2 gene was identified in a family with autosomal dominant severe insulin resistance, diabetes mellitus and partial lipodystrophy.

PMID:17327441 - Of 94 probands with severe insulin resistance (35 of which had partial lipodystrophy) that were screened for AKT2 variants, one female identified with p.Arg467Trp variant was reported with type 2 diabetes and partial lipodystrophy, while another female identified with p.Arg208Lys variant had severe insulin resistance and acanthosis nigricans. p.Arg467Trp was present in neither 47 ethnically matched control subjects nor in 2 unaffected sons of the carrier. p.Arg208Lys variant was not present in her affected son but was present in 1 of 47 white control subjects.

PMID:12843127 - Functional studies in mice showed that loss of AKT2 results in severe diabetes, age-dependent lipoatrophy and mild growth deficiency.

Created: 2 Aug 2023, 6:14 p.m. | Last Modified: 2 Aug 2023, 6:14 p.m.

Panel Version: 4.6

This review was provided by NHSE Genomic Medicine Service for inclusion of this gene in this panel:
A causal role for a R274H variant in Akt2 was demonstrated here PMID: 15166380, where the variant co-segregated with severe insulin resistance, partial lipodystrophy and type 2 diabetes. Akt2 knockout mice develop an analogous age-dependent partial lipoatrophy (PMID: 12843127), and Akt2 is a canonical effector of insulin signalling. Akt2 is currently analysed and reported as part of assessment for Monogenic diabetes (R141) on the strength of this evidence. It has been endorsed as a cause of lipodystrophy by an international multi-society practice guideline (PMID: 27710244)

Created: 2 Aug 2023, 11:38 a.m. | Last Modified: 2 Aug 2023, 11:38 a.m.

Panel Version: 4.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Severe insulin resistance, familial partial lipodystrophy

Publications

• 12843127
• 15166380
• 17327441
• 27710244

Comment when marking as ready: AKT2 was included in the gene list as suggested by Kevin Colclough (Royal Devon & Exeter Hospital). AKT2 is a red gene in the Insulin resistance (including lipodystrophy) (Version 1.6) panel and only 1 variant has been reported when this gene was reviewed for that panel (2016). There has not been any new variants for this gene.

Created: 7 Jan 2019, 11:21 a.m.

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Comment when marking as ready: Associated with phenotype in OMIM, not in G2P. Only one LOF variant reported

Created: 12 Aug 2016, 3:13 p.m.

Comment on publications: 17327441 questions relevance of AKT2 LOF variants for type 2 diabetes risk, while 11387480 examining a mouse model supports the involvement of AKT in normal glucose homeostasis.

Created: 12 Aug 2016, 3:04 p.m.

Comment on phenotypes: Also associated with Hypoinsulinemic hypoglycemia with hemihypertrophy 240900

Created: 11 Aug 2016, 1 p.m.