Submissions for variant NM_005465.7(AKT3):c.1393C>T (p.Arg465Trp)

dbSNP: rs587776935

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415230	SCV000492960	likely pathogenic	Global developmental delay; Polymicrogyria; Macrocephaly; Capillary hemangioma	2014-01-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622431	SCV000742941	likely pathogenic	Inborn genetic diseases	2017-10-04	criteria provided, single submitter	clinical testing
Invitae	RCV000033035	SCV000835228	pathogenic	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2	2022-10-24	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 AKT3 function (PMID: 22729224, 23745724, 24705253). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 39814). This missense change has been observed in individual(s) with overlapping features of megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) (PMID: 22729224, 23745724). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 465 of the AKT3 protein (p.Arg465Trp).
CeGaT Center for Human Genetics Tuebingen	RCV001532107	SCV001747509	pathogenic	not provided	2021-03-01	criteria provided, single submitter	clinical testing
3billion	RCV000033035	SCV002012138	pathogenic	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (PMID: 23745724, 22729224, PS2, PS4_M). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2. Missense changes are a common disease-causing mechanism (PP2). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV001532107	SCV002318995	pathogenic	not provided	2022-03-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that R465W caused increased activity compared to wild-type AKT3 (Alcantara et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28475857, 28973083, 29286531, 32446860, 33942996, 33176815, 31785789, 22729224, 23592320, 25140959, 28969385)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251942	SCV002523303	pathogenic	See cases	2019-10-18	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS2, PS4, PM2, PP2, PP3
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000033035	SCV002557824	pathogenic	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (MPPH) (MIM#615937) (GeneReviews). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated kinase C-terminal domain (DECIPHER, Uniprot). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least five patients, including proven de novo events, and has been classified as pathogenic by diagnostic laboratories in ClinVar (DECIPHER; PMID: 22729224, 29286531, 33176815). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000033035	SCV003804256	pathogenic	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2	2023-01-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000033035	SCV003924393	pathogenic	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2	2023-05-16	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. de novo Selected ACMG criteria: Pathogenic (II):PP3;PP2;PM2;PS4;PS2
PreventionGenetics, part of Exact Sciences	RCV003398588	SCV004119597	pathogenic	AKT3-related condition	2022-12-07	criteria provided, single submitter	clinical testing	The AKT3 c.1393C>T variant is predicted to result in the amino acid substitution p.Arg465Trp. This variant has been reported de novo in multiple individuals with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (Rivière et al. 2012. PMID: 22729224, Table 1 Alacantara et al. 2017. PMID: 28969385, eTable 3 Meng et al. 2017. PMID: 28973083, S Table 1 Tumiene et al. 2018. PMID: 29286531, Table 1 Lin et al. 2020 PMID: 33176815, Results section 3.3.2 Moirangthem et al 2021 PMID: 33942996.) This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
OMIM	RCV000033035	SCV000056815	pathogenic	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2	2012-06-24	no assertion criteria provided	literature only
GeneReviews	RCV000033035	SCV000328925	not provided	Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2		no assertion provided	literature only