Variant: NM_005465.7(AKT3):c.49G>A (p.Glu17Lys)

CA130584

39816 (ClinVar)

Gene: AKT3

Condition: overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

Inheritance Mode: Autosomal dominant inheritance (mosaic)

UUID: 0c491a99-6d6d-43fa-8837-da81e69e236b

Approved on: 2022-02-12

Published on: 2022-02-12

HGVS expressions

NM_005465.7:c.49G>A
NM_005465.7(AKT3):c.49G>A (p.Glu17Lys)
NC_000001.11:g.243695714C>T
CM000663.2:g.243695714C>T
NC_000001.10:g.243859016C>T
CM000663.1:g.243859016C>T
NC_000001.9:g.241925639C>T
NG_029764.1:g.152871G>A
NG_029764.2:g.160366G>A
ENST00000263826.12:c.49G>A
ENST00000366539.6:c.49G>A
ENST00000491219.6:n.43G>A
ENST00000492957.2:n.49G>A
ENST00000552631.2:n.163G>A
ENST00000672238.1:c.49G>A
ENST00000672442.1:c.49G>A
ENST00000672578.1:c.-135G>A
ENST00000672679.1:n.6G>A
ENST00000673400.1:c.49G>A
ENST00000673466.1:c.49G>A
ENST00000680056.1:n.47-30831G>A
ENST00000680118.1:c.49G>A
ENST00000681794.1:n.49G>A
ENST00000263826.9:c.49G>A
ENST00000336199.9:c.49G>A
ENST00000366539.5:c.49G>A
ENST00000366540.5:c.49G>A
ENST00000463991.5:n.187G>A
ENST00000490018.1:n.541G>A
ENST00000491219.5:n.3G>A
ENST00000552631.1:c.49G>A
NM_001206729.1:c.49G>A
NM_005465.4:c.49G>A
NM_181690.2:c.49G>A
NM_005465.5:c.49G>A
NM_001370074.1:c.49G>A
NM_001206729.2:c.49G>A

Pathogenic

• Met criteria codes: PS2_Moderate PM2_Supporting PM1_Supporting PS4 PP2 PS3_Supporting

• Not Met criteria codes: BS2 PVS1 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS1 PP4 PP1 PP3 BA1 PM6 PM3 PM4 PM5

Expert Panel

Brain Malformations VCEP

Criteria Specification Information

Evidence submitted by expert panel

Brain Malformations VCEP

The c.49G>A (NM_005465.7) variant in AKT3 is a missense variant predicted to cause substitution of (p.Glu17Lys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). AKT3, in which the variant was identified, is defined by the ClinGen Brain Malformations Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant resides within the pleckstrin homology domain of AKT3 that is defined as a critical functional domain by the ClinGen BMEP (PMID: 28969385) (PM1_Supporting). This variant has been shown to significantly increase phosphorylation levels in experiments with case and control cells of similar isogenic backgrounds indicating that this variant impacts protein function (PMID: 18813315) (PS3_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4; PMIDs: 28969385, 22500628, 22729223; identified in 4 individuals with neuroimaging demonstrating at least one large cerebral hemisphere with cortical malformation(s) and 7 tumor samples in the literature and COSMIC). Testing of unaffected and affected tissue show variable allelic fractions consistent with a post-zygotic event (PS2_Moderate; PMID: 22500628). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PP2, PM1_P, PS3_P, PS4, PS2_M; 10 points (VCEP specifications version 1; Approved: 1/31/2021)

Met criteria codes

• PM2_Supporting: absent from gnomAD and ExAC
• PM1_Supporting: pleckstrin homology domain
• PS4: In 7 COSMIC tumor samples
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Not Met criteria codes

• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline