NM_005465.7(AKT3):c.1393C>T (p.Arg465Trp) AND Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: May 16, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000033035.27

Allele description [Variation Report for NM_005465.7(AKT3):c.1393C>T (p.Arg465Trp)]

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

Gene:

AKT3:AKT serine/threonine kinase 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q44

Genomic location:

Preferred name:

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

HGVS:

NC_000001.11:g.243505296G>A
NG_029764.2:g.350784C>T
NM_001206729.2:c.1355-5510C>T
NM_001370074.1:c.1393C>T
NM_005465.7:c.1393C>TMANE SELECT
NM_005465.7:c.1393C>T
NM_181690.2:c.1355-5510C>T
NP_001357003.1:p.Arg465Trp
NP_005456.1:p.Arg465Trp
LRG_1396t1:c.1393C>T
LRG_1396:g.350784C>T
LRG_1396p1:p.Arg465Trp
NC_000001.10:g.243668598G>A
NM_005465.4:c.1393C>T
Q9Y243:p.Arg465Trp

Protein change:

R465W; ARG465TRP

Links:

UniProtKB: Q9Y243#VAR_069261; OMIM: 611223.0001; dbSNP: rs587776935

NCBI 1000 Genomes Browser:

rs587776935

Molecular consequence:

NM_001206729.2:c.1355-5510C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_181690.2:c.1355-5510C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001370074.1:c.1393C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005465.7:c.1393C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (MPPH2)
Synonyms:: MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 2, SOMATIC
Identifiers:: MONDO: MONDO:0014407; MedGen: C4014738; Orphanet: 83473; OMIM: 615937

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000056815	OMIM	no assertion criteria provided	Pathogenic (Jun 24, 2012)	germline	literature only	PubMed (1) [See all records that cite this PMID] Mirzaa, G. M., Conway, R. L., Gripp, K. W., Lerman-Sagie, T., Siegel, D. H., deVries, L. S., Lev, D., Kramer, N., Hopkins, E., Graham, J. M., Jr., Dobyns, W. B. Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. Am. J. Med. Genet. 158A: 269-291, 2012.,
SCV000328925	GeneReviews	no classification provided	not provided	germline	literature only
SCV000835228	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 24, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24705253, 22729224, 23745724, 28492532
SCV002012138	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23745724, 22729224, 25741868
SCV002557824	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22729224, 29286531, 33176815, 25741868
SCV003804256	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 23, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003924393	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	criteria provided, single submitter (Hauer et al. (Genet Med. 2018))	Pathogenic (May 16, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing, literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.

Mirzaa G, Parry DA, Fry AE, Giamanco KA, Schwartzentruber J, Vanstone M, Logan CV, Roberts N, Johnson CA, Singh S, Kholmanskikh SS, Adams C, Hodge RD, Hevner RF, Bonthron DT, Braun KPJ, Faivre L, Rivière JB, St-Onge J, Gripp KW, Mancini GM, Pang K, et al.

Nat Genet. 2014 May;46(5):510-515. doi: 10.1038/ng.2948. Epub 2014 Apr 6.

PubMed [citation]

PMID:: 24705253
PMCID:: PMC4004933

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000056815.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Riviere et al. (2012) performed exome sequencing in an individual with clinical features overlapping megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-2 (MPPH2; 615937) and megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP; 602501) and identified a de novo 1393C-T transition in the AKT3 gene, resulting in an arg465-to-trp (R465W) substitution. The mutation was not found in his parents. This patient (LR08-018) had previously been reported by Mirzaa et al. (2012). Also see 611223.0002.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000328925.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000835228.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002012138.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557824.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV003804256.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, SCV003924393.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

This variant has been identified by standard clinical testing. de novo Selected ACMG criteria: Pathogenic (II):PP3;PP2;PM2;PS4;PS2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jul 7, 2024

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