ClinVar Miner

Submissions for variant NM_005465.7(AKT3):c.49G>A (p.Glu17Lys)

dbSNP: rs397514606
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Brain Malformations Variant Curation Expert Panel RCV001836719 SCV001949963 pathogenic Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes 2022-02-12 reviewed by expert panel curation 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)
OMIM RCV000033037 SCV000056817 pathogenic Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 2012-06-24 no assertion criteria provided literature only

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