AKT2

Inheritance Pattern: AD

Disease ID:MONDO:0007455

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0009416

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0009416

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0019192

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0005148

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0009416

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0009416

Submitter: ClinGen

*AKT2* was first reported in relation to hypoinsulinemic hypoglycemia with body hemihypertrophy in 2011 by Hussain et al. (PMID: 21979934). This report described three unrelated children with unexplained, recurrent and severe fasting hypoglycemia and asymmetrical overgrowth. All patients carried the same de novo variant in *AKT2* (NM_001626.6; c.49G>A; (p.Glu17Lys)), in two cases as heterozygotes and, in one case, in mosaic form (20% variant allele frequency). The mild left hemihypertrophy became less evident with age. Two of them developed obesity, likely from overfeeding, while one avoided it. Two of the originally reported patients were re-studied at 17 years old. At this age both were independent of percutaneous feeding overnight, one showed evidence of resolution of fasting hypoglycemia, while the other showed persisting hypoglycemic tendency (PMID: 28541532). Since then, the same variant (p.Glu17Lys) has been reported in at least 6 additional patients with hypoinsulinemic hypoglycemia and hemihypertrophy (PMIDs: 24285683, 26003998, 35602880, 38344362). Genetic evidence score: 8 points. The mechanism of pathogenicity is reported to be gain of function, evidenced by in vitro functional assays showing that the *AKT*2 Glu17Lys disrupts the interaction between the pleckstrin homology (PH) domain and the kinase domain of *AKT2*. This causes the kinase to be constitutively recruited to the plasma membrane and activated without the need for insulin binding to its receptor (PMIDs: Arya et al., 24285683; Hussain et al., 21979934; Siklar et al. 32157856). This leads to continuous, low level activation of downstream insulin signaling, mimicking the effects of insulin even when insulin is absent or undetectable in the blood (PMIDs: Arya et al., 24285683; Hussain et al., 21979934; Siklar et al. 32157856). As a result, lipolysis and ketogenesis are inhibited, and hepatic gluconeogenesis is suppressed, with effects on glucose uptake into muscle and adipose tissue not yet determined —the net effect is to produce a biochemical profile identical to that of hyperinsulinism (hypoketotic, hypo-fatty-acidemic hypoglycemia), but with lower requirement for glucose infusion to maintain euglycemia, and, importantly, without elevated insulin or C-peptide levels (PMIDs: Arya et al., 24285683; Hussain et al., 21979934; Siklar et al. 32157856). Summary of experimental data: 3.5 points. Total score for genetic evidence and experimental evidence: 11.5 points. A single variant in *AKT2* (NM_001626:6: c.821G>A, p.Arg274His)) has been reported in only one family with FPLD (PMID: 15166380). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanisms and phenotypic variability underlying *AKT2*-related disease entities. Therefore, the curation of *AKT2* has been split into: i) *AKT2*-related FPLD (MONDO:0019192), included in this curation and ii) hypoinsulinemic hypoglycemia and body hemihypertrophy (HHBH, MONDO:0009416). In summary, current genetic and functional evidence supporting the human gene-disease relationship between *AKT2* (currently p.Glu17Lys variant only) and HHBH are definitive. Although this gene/variant causes hypo- rather than hyperinsulinism, similarities in phenotype warrant inclusion on a testing panel for hyperinsulinism. The possibility of mosaicism for this variant should be considered. An apparent negative result in the presence of strong clinical suspicion of HHBH warrants more targeted interrogation of the variant. This classification was approved by the MDGCEP on March 4, 2026. Gene Clinical Validity Standard Operating Procedures (SOP) - SOP12.

Inheritance Pattern: AD

Disease ID:MONDO:0009416

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0019192

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0019192

Submitter: ClinGen

*AKT2* was first reported in relation to autosomal dominant familial partial lipodystrophy (FPLD) in 2004 (George et al., PMID: 15166380). George et al. described a rare, highly penetrant *AKT2* mutation (NM_001626:6:c.821G>A, p.Arg274His) in a single kindred, co-segregating with insulin resistance in four individuals across three generations. Three of these also had diabetes, and the proband assessed in more detail showed reduced body fat compared to that predicted for height and weight. Two affected family members assessed later showed increased TG-enriched VLDL, hypertriglyceridemia, low HDL cholesterol levels, low leptin and adiponectin concentrations, while one assessed further also showed increased de novo lipogenesis and liver fat content (Semple et al., PMID: 19164855). No other penetrant disease-associated *AKT2* alleles have been described in the literature, but at the population level, a rare coding variant (c.148C>A, p.Pro50Thr, rs184042322, gnomAD v4.1 Grpmax FAF = 0.000038) has been reported at higher frequency in the Finnish population (MAF = 0.012) than other populations. This variant is not associated with classic Mendelian disease but has measurable associations with metabolic traits and type 2 diabetes risk at the population level and demonstrated a mild deleterious impact on function in vitro (PMIDs: 28341696, 29141982, 36409629). Genetic evidence score: 0.5 points. The mechanism of pathogenicity is reported to be loss of function, evidenced by in vitro functional assays showed that the *AKT2* Arg274His allele has little or no kinase activity. Limited evidence from reporter assays also raises the possibility of a dominant negative activity of the mutant allele (PMID: 15166380). AKT2 signaling is also important for adipocyte differentiation (PMID: 15166380). Akt2 knockout mice developed severe diabetes with age dependent partial lipoatrophy (PMIDs:12843127, 11387480). Also, Adipo-AKT-KO mice (PMID: 27408773) recapitulate many of the features observed in FPLD caused by the LoF variant p.Arg274His, including insulin resistance and hepatomegaly. Summary of experimental data: 5.5 points. Total score for genetic evidence and experimental evidence: 6 points. A single variant in *AKT2* (c.49G>A, p.Gly17Lys) has been reported in individuals with hypoinsulinemic hypoglycemia, some with mild hemihypertrophy (PMIDs: 21979934, 24285683, 26003998, 35602880, 38344362, 34673243). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanisms and phenotypic variability underlying *AKT2*-related disease entities. Therefore, the curation of *AKT2* has been split into: i) AKT2-related FPLD (MONDO:0019192), included in this curation and ii) hypoinsulinemic hypoglycemia and body hemihypertrophy (HIHGHH, MONDO:0009416). In summary, while the mechanistic link between AKT2 dysfunction and lipodystrophic insulin resistance is highly plausible and well evidenced, current genetic evidence supporting the human gene-disease relationship is limited. This classification was approved by the MDGCEP on January 14, 2026. Gene Clinical Validity Standard Operating Procedures (SOP) - SOP11.