ClinVar Genomic variation as it relates to human health
NM_005465.7(AKT3):c.1393C>T (p.Arg465Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Variant Details
- Identifiers
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NM_005465.7(AKT3):c.1393C>T (p.Arg465Trp)
Variation ID: 39814 Accession: VCV000039814.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q44 1: 243505296 (GRCh38) [ NCBI UCSC ] 1: 243668598 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 24, 2014 Aug 25, 2024 May 16, 2023 Somatic - Oncogenicity Aug 11, 2024 Aug 11, 2024 Jul 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005465.7:c.1393C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005456.1:p.Arg465Trp missense NM_001206729.2:c.1355-5510C>T intron variant NM_001370074.1:c.1393C>T NP_001357003.1:p.Arg465Trp missense NM_181690.2:c.1355-5510C>T intron variant NC_000001.11:g.243505296G>A NC_000001.10:g.243668598G>A NG_029764.2:g.350784C>T LRG_1396:g.350784C>T LRG_1396t1:c.1393C>T LRG_1396p1:p.Arg465Trp Q9Y243:p.Arg465Trp - Protein change
- R465W
- Other names
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- Canonical SPDI
- NC_000001.11:243505295:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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AKT3 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
178 | 351 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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May 16, 2023 | RCV000033035.28 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 6, 2014 | RCV000415230.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 4, 2017 | RCV000622431.10 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 27, 2022 | RCV001532107.26 | |
See cases
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Pathogenic (1) |
criteria provided, single submitter
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Oct 18, 2019 | RCV002251942.9 |
AKT3-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Dec 7, 2022 | RCV004532479.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 18, 2019)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523303.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
ACMG classification criteria: PS2, PS4, PM2, PP2, PP3
Clinical Features:
Overgrowth (present) , Neurodevelopmental abnormality (present) , Macrocephaly (present) , Cognitive impairment (present)
Geographic origin: Brazil
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Pathogenic
(Jan 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2
Affected status: yes
Allele origin:
germline
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV003804256.1
First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023 |
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Pathogenic
(Mar 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002318995.2
First in ClinVar: Apr 02, 2022 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Oct 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000835228.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
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). … (more)
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). (less)
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557824.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
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 … (more)
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 (less)
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Pathogenic
(Mar 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001747509.18
First in ClinVar: Jul 10, 2021 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(Jan 06, 2014)
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criteria provided, single submitter
Method: clinical testing
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Capillary hemangioma
Global developmental delay Macrocephaly Polymicrogyria
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492960.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Pathogenic
(Oct 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002012138.1
First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Macrocephaly (present) , Seizure (present) , Ventriculomegaly (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Hydrocephalus (present) , Premature … (more)
Macrocephaly (present) , Seizure (present) , Ventriculomegaly (present) , Delayed fine motor development (present) , Delayed gross motor development (present) , Hydrocephalus (present) , Premature birth (present) , Delayed speech and language development (present) , Polymicrogyria (present) , Strabismus (present) , Thick corpus callosum (present) (less)
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Likely pathogenic
(Oct 04, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000742941.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Observation 1:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: El Salvadorian/Italian/Irish
Observation 2:
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Eastern European/Russian/Lithuanian/Czech/English
Observation 3:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Danish/Irish/Welsh/German/Canadian
Observation 4:
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Intellectual disability (present) , Microcephaly (present) , Autistic disorder of childhood onset (present) , Heart murmur (present) , Frontal bossing … (more)
Global developmental delay (present) , Intellectual disability (present) , Microcephaly (present) , Autistic disorder of childhood onset (present) , Heart murmur (present) , Frontal bossing (present) , Midface retrusion (present) , Heterotopia (present) , Cerebellar malformation (present) (less)
Sex: female
Ethnicity/Population group: Hispanic
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Pathogenic
(May 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Accession: SCV003924393.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Comment:
This variant has been identified by standard clinical testing. de novo Selected ACMG criteria: Pathogenic (II):PP3;PP2;PM2;PS4;PS2
Number of individuals with the variant: 1
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Pathogenic
(Dec 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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AKT3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119597.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(May 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005196923.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(Jun 24, 2012)
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no assertion criteria provided
Method: literature only
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MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000056815.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 15, 2021 |
Comment on evidence:
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 … (more)
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. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000328925.2
First in ClinVar: Nov 22, 2016 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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MPPH Syndrome. | Adam MP | - | 2022 | PMID: 27854409 |
Clinical and genetic characteristics and prenatal diagnosis of patients presented GDD/ID with rare monogenic causes. | Lin L | Orphanet journal of rare diseases | 2020 | PMID: 33176815 |
Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice. | Tumienė B | Clinical genetics | 2018 | PMID: 29286531 |
Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly. | Alcantara D | Brain : a journal of neurology | 2017 | PMID: 28969385 |
De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. | Mirzaa G | Nature genetics | 2014 | PMID: 24705253 |
AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH. | Nakamura K | Clinical genetics | 2014 | PMID: 23745724 |
De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. | Rivière JB | Nature genetics | 2012 | PMID: 22729224 |
Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. | Mirzaa GM | American journal of medical genetics. Part A | 2012 | PMID: 22228622 |
Conditions - Somatic
Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
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Likely oncogenic
criteria provided, single submitter
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Jul 31, 2024 | RCV004668745.1 |
Submissions - Somatic
Oncogenicity
Help
The submitted oncogenicity classification for each SCV record. (Last evaluated) |
Review Status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. |
Tumor type
Help
The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely oncogenic
(Jul 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Neoplasm
Affected status: unknown
Allele origin:
somatic
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094231.1
First In ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
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Citations for somatic classification of this variant
HelpThere are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs587776935 ...
HelpRecord last updated Sep 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.