ClinVar Miner

Submissions for variant NM_001382430.1(AKT1):c.49G>A (p.Glu17Lys)

dbSNP: rs121434592
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Total submissions: 26
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000795313 SCV000934768 pathogenic Cowden syndrome 6 2022-01-02 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects AKT1 function (PMID: 17611497, 18954143, 21793738, 23237847). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 13983). This missense change has been observed in individuals with Proteus syndrome (PMID: 21793738). This variant is present in population databases (rs121434592, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 17 of the AKT1 protein (p.Glu17Lys).
GeneDx RCV001813745 SCV002061056 pathogenic not provided 2022-01-06 criteria provided, single submitter clinical testing Published functional studies demonstrate that E17K is a gain-of-function variant, as E17K produced increased Akt1 activation and downstream signaling compared with wild type (Yi et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in biopsy samples of patients with Proteus syndrome (Lindhurst et al., 2011); This variant is associated with the following publications: (PMID: 30103035, 26872686, 29681107, 17611497, 21793738, 23237847, 18954143, 25782637, 32617723, 33442022, 33030203, 33303690)
Clinical Genomics Laboratory, Washington University in St. Louis RCV000031926 SCV004176945 pathogenic Proteus syndrome 2023-10-31 criteria provided, single submitter clinical testing An AKT1 c.49G>A (p.Glu17Lys) variant was identified at an allelic fraction that is consistent with somatic origin. This variant has been reported in numerous individuals with Proteus syndrome (Lindhurst MJ et al., PMID: 21793738; Wee JS et al., PMID: 24850616; Pithadia DJ et al., PMID: 32035943; Schmidt J et al., PMID: 35670639; McNulty SN et al. PMID: 31585106) and in numerous types of cancer in the cancer database COSMIC (Genomic mutation ID: COSV62571334). It has been reported in the ClinVar database as a pathogenic variant by two submitters (ClinVar ID: 13983). The AKT1 c.49G>A (p.Glu17Lys) variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. It resides within a region, the pleckstrin homology domain, of AKT1 that is defined as a critical functional domain (Shoji K et al. PMID:19491896). Functional studies show that the AKT1 c.49G>A (p.Glu17Lys) variant significantly activates AKT1 phosphorylation and signaling in patient cell lines and animal models, indicating that this variant impacts protein function (Lindhurst MJ et al., PMID: 21793738; Blum N, Harris MP., PMID: 36621776). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the AKT1 c.49G>A (p.Glu17Lys) variant is classified as pathogenic.
OMIM RCV000015017 SCV000035273 pathogenic Breast adenocarcinoma 2011-08-18 no assertion criteria provided literature only
OMIM RCV000015018 SCV000035274 pathogenic Carcinoma of colon 2011-08-18 no assertion criteria provided literature only
OMIM RCV000015019 SCV000035275 pathogenic Neoplasm of ovary 2011-08-18 no assertion criteria provided literature only
OMIM RCV000031926 SCV000043964 pathogenic Proteus syndrome 2011-08-18 no assertion criteria provided literature only
GeneReviews RCV000031926 SCV000054577 not provided Proteus syndrome no assertion provided literature only
Database of Curated Mutations (DoCM) RCV000431237 SCV000504510 likely pathogenic Endometrial Endometrioid Adenocarcinoma, Variant with Squamous Differentiation 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436698 SCV000504511 pathogenic Non-small cell lung carcinoma 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419412 SCV000504512 likely pathogenic Prostate adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430173 SCV000504513 pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440828 SCV000504514 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421850 SCV000504515 likely pathogenic Small cell lung carcinoma 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429060 SCV000504516 pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439982 SCV000504517 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421009 SCV000504518 likely pathogenic Thyroid tumor 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431723 SCV000504519 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445271 SCV000504520 likely pathogenic Prostate neoplasm 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421696 SCV000504521 likely pathogenic Bone osteosarcoma 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434120 SCV000504522 likely pathogenic Tumor of meninges 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444311 SCV000504523 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427484 SCV000504524 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438154 SCV000504525 likely pathogenic Neoplasm of uterine cervix 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443761 SCV000504526 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426386 SCV000504527 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only

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