Variant Detail

Variant Information
ID
DPV: 381
Chromosome
1
Gene
HGVS (GRCh37/hg19)
NC_000001.10:g.243776983T>C
HGVS (GRCh38/hg38)
NC_000001.11:g.243613681T>C
HGVS (RNA)
NM_005465.4:c.686A>G
HGVS (Protein)
NP_859029:p.N229S
dbSNP
-
ClinGen Allele Registry
CA130581
Allele Frequency
Individual Information

ID
DPVS:25.1
Clinical Significance
Pathogenic
Date Last Evaluated
2017-03-30
Clinical Significance Citation
Riviere, J. B. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. 2012 Nat Genet. 2012 Jun 24;44(8):934-40. doi: 10.1038/ng.2331. PMID:22729224
Nakamura, K. AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH. 2014 Clin Genet. 2014 Apr;85(4):396-8. doi: 10.1111/cge.12188. Epub 2013 Jun 10. PMID:23745724
Harada, A. Sudden death in a case of megalencephaly capillary malformation associated with a de novo mutation in AKT3. 2015 Childs Nerv Syst. 2015 Mar;31(3):465-71. doi: 10.1007/s00381-014-2589-y. Epub 2014 Nov 22. PMID:25416470
Nellist, M. Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia. 2015 Mol Genet Metab. 2015 Mar;114(3):467-73. doi: 10.1016/j.ymgme.2014.11.018. Epub 2014 Dec 5. PMID:25523067
Mirzaa, G. MPPH Syndrome 1993 PMID:27854409
Negishi, Y. A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly. 2017 BMC Med Genet. 2017 Jan 13;18(1):4. doi: 10.1186/s12881-016-0363-6. PMID:28086757

Harada A. et al. Childs Nerv. Syst. 31, 465-471 (2015).

Transcript
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Disease

megalencephaly capillary malformation (MCAP)

Phenotype
-
Zygosity
single heterozygote
Allele Origin
de novo
Affected Status
yes
Sample Type
  • DNA
Analysis Type
  • Next-Generation Sequencing - Illumina/Solexa
Collection Method
literature only
Compound heterozygous variant(s)
Data Submitter
Comment
Targeted resequencing (284 neural genes)

ID
DPVS:26.1
Clinical Significance
Pathogenic
Date Last Evaluated
2017-03-30
Clinical Significance Citation
Negishi, Y. A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly. 2017 BMC Med Genet. 2017 Jan 13;18(1):4. doi: 10.1186/s12881-016-0363-6. PMID:28086757

Negishi Y. et al. BMC Med. Genet. in press (2017).

Transcript
-
Disease

megalencephaly

Phenotype
-
Zygosity
single heterozygote
Allele Origin
de novo
Affected Status
yes
Sample Type
  • DNA
Analysis Type
  • Next-Generation Sequencing
Collection Method
literature only
Compound heterozygous variant(s)
Data Submitter
Comment
WES with SureSelect V4

ID
DPVS:5947.1
Clinical Significance
Pathogenic
Date Last Evaluated
2018-12-04
Clinical Significance Citation
Negishi, Y. A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly. 2017 BMC Med Genet. 2017 Jan 13;18(1):4. doi: 10.1186/s12881-016-0363-6. PMID:28086757
Nakamura, K. AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH. 2014 Clin Genet. 2014 Apr;85(4):396-8. doi: 10.1111/cge.12188. Epub 2013 Jun 10. PMID:23745724
Harada, A. Sudden death in a case of megalencephaly capillary malformation associated with a de novo mutation in AKT3. 2015 Childs Nerv Syst. 2015 Mar;31(3):465-71. doi: 10.1007/s00381-014-2589-y. Epub 2014 Nov 22. PMID:25416470

Negishi et al. BMC Med Genet 18:4, 2017

Transcript
-
Disease

Megalencephaly

Phenotype
-
Zygosity
single heterozygote
Allele Origin
germline
Affected Status
yes
Sample Type
  • DNA
Analysis Type
  • SEQuencing
Collection Method
literature only
Compound heterozygous variant(s)
Data Submitter
Comment
-

ClinVar
Model Animals
VCF
VCF (GRCh37/hg19) 
											##fileformat=VCFv4.0
##reference=GRCh37
##INFO=<ID=CLNALLELEID,Number=1,Type=Integer,Description="the ClinVar Allele ID">
##INFO=<ID=CLNDISDB,Number=.,Type=String,Description="Tag-value pairs of disease database name and identifier, e.g. OMIM:NNNNNN (from ClinVar)">
##INFO=<ID=CLNDN,Number=.,Type=String,Description="ClinVar's preferred disease name for the concept specified by disease identifiers in CLNDISDB (from ClinVar)">
##INFO=<ID=CLNHGVS,Number=.,Type=String,Description="Top-level (primary assembly, alt, or patch) HGVS expression.(from ClinVar)">
##INFO=<ID=CLNSIG,Number=.,Type=String,Description="Clinical significance for this single variant (from ClinVar)">
##INFO=<ID=EXAC_AC,Number=A,Type=Integer,Description="Allele count in genotypes, for each ALT allele, in the same order as listed (from ExAC r1)">
##INFO=<ID=EXAC_AF,Number=A,Type=Float,Description="Allele Frequency, for each ALT allele, in the same order as listed (from ExAC r1)">
##INFO=<ID=EXAC_AN,Number=1,Type=Integer,Description="Total number of alleles in called genotypes (from ExAC r1)">
##INFO=<ID=EXAC_FILTER,Number=1,Type=String,Description="calculated by self of overlapping values in field FILTER (from ExAC r1)">
##INFO=<ID=GNOMAD_AC,Number=A,Type=Integer,Description="Allele count in genotypes, for each ALT allele, in the same order as listed (from gnomAD v2.1.1 )">
##INFO=<ID=GNOMAD_AF,Number=A,Type=Float,Description="Allele Frequency, for each ALT allele, in the same order as listed (from gnomAD v2.1.1 )">
##INFO=<ID=GNOMAD_AN,Number=1,Type=Integer,Description="Total number of alleles in called genotypes (from gnomAD v2.1.1 )">
##INFO=<ID=HGVD_AAF,Number=A,Type=Float,Description="Alternative Allele Frequency(s) NA/(NR+NAtotal) (from HGVD/DBexome20170802)">
##INFO=<ID=HGVD_AC,Number=A,Type=Integer,Description="number(s) of alternative allele(s) (from HGVD/DBexome20170802)">
##INFO=<ID=HGVD_NR,Number=1,Type=Integer,Description="number of reference allele (from HGVD/DBexome20170802)">
##INFO=<ID=TOMMO_4_7K_AC,Number=A,Type=Integer,Description="Allele count in genotypes (from ToMMo 4.7KJPN (20190826))">
##INFO=<ID=TOMMO_4_7K_AF,Number=A,Type=Float,Description="Allele frequency, for each ALT allele, in the same order as listed  (from ToMMo 4.7KJPN (20190826))">
##INFO=<ID=TOMMO_4_7K_AN,Number=1,Type=Integer,Description="Total number of alleles in called genotypes (from ToMMo 4.7KJPN (20190826))">
##INFO=<ID=dbSNP_RSID,Number=1,Type=String,Description="dbSNP ID (from dbSNP b151 )">
##INFO=<ID=GENEINFO,Number=1,Type=String,Description="Pairs each of gene symbol:gene id. The gene symbol and id are delimited by a colon (:)">
##INFO=<ID=DPVID,Number=.,Type=String,Description="DPV Variant ID">
##INFO=<ID=DPVSIG,Number=.,Type=String,Description="Variant Clinical Significance">
##INFO=<ID=DPVDSDBID,Number=.,Type=String,Description="Variant disease database ID">
##INFO=<ID=DPVDBN,Number=.,Type=String,Description="Variant disease name">
##INFO=<ID=DPVHGVS,Number=.,Type=String,Description="Variant in HGVS.">
#CHROM	POS	ID	REF	ALT	QUAL	FILTER	INFO
1	243776983	NC_000001.10:g.243776983T>C	T	C	.	.	CLNALLELEID=48414;CLNDN=Megalencephaly-capillary_malformation-polymicrogyria_syndrome|Megalencephaly-polymicrogyria-polydactyly-hydrocephalus_syndrome_2;CLNDISDB=MONDO:MONDO:0011240,MedGen:C1865285,OMIM:602501,Orphanet:ORPHA60040|MONDO:MONDO:0014407,MedGen:C4014738,OMIM:615937;CLNSIG=Pathogenic;CLNHGVS=NC_000001.10:g.243776983T>C;GENEINFO=393:10000;DPVID=381;DPVSIG=Pathogenic;DPVDSDBID=OMIM:615937;DPVDBN=Megalencephaly-polymicrogyria-polydactyly-hydrocephalus_syndrome_2;DPVHGVS=NC_000001.10:g.243776983T>C	.
VCF (GRCh38/hg38) 
											##fileformat=VCFv4.0
##reference=GRCh38
##INFO=<ID=CLNALLELEID,Number=1,Type=Integer,Description="the ClinVar Allele ID">
##INFO=<ID=CLNDISDB,Number=.,Type=String,Description="Tag-value pairs of disease database name and identifier, e.g. OMIM:NNNNNN (from ClinVar)">
##INFO=<ID=CLNDN,Number=.,Type=String,Description="ClinVar's preferred disease name for the concept specified by disease identifiers in CLNDISDB (from ClinVar)">
##INFO=<ID=CLNHGVS,Number=.,Type=String,Description="Top-level (primary assembly, alt, or patch) HGVS expression.(from ClinVar)">
##INFO=<ID=CLNSIG,Number=.,Type=String,Description="Clinical significance for this single variant (from ClinVar)">
##INFO=<ID=GNOMAD_AC,Number=A,Type=Integer,Description="Allele count in genotypes, for each ALT allele, in the same order as listed (from gnomAD v2.1.1 )">
##INFO=<ID=GNOMAD_AF,Number=A,Type=Float,Description="Allele Frequency, for each ALT allele, in the same order as listed (from gnomAD v2.1.1 )">
##INFO=<ID=GNOMAD_AN,Number=1,Type=Integer,Description="Total number of alleles in called genotypes (from gnomAD v2.1.1 )">
##INFO=<ID=dbSNP_RSID,Number=1,Type=String,Description="dbSNP ID (from dbSNP b151 )">
##originalFile=</tmp/crossmap-input-5zbin1pe>
##targetRefGenome=</usr/lib64/python2.7/site-packages/transvar/transvar.download/hg38.fa>
##INFO=<ID=GENEINFO,Number=1,Type=String,Description="Pairs each of gene symbol:gene id. The gene symbol and id are delimited by a colon (:)">
##INFO=<ID=DPVID,Number=.,Type=String,Description="DPV Variant ID">
##INFO=<ID=DPVSIG,Number=.,Type=String,Description="Variant Clinical Significance">
##INFO=<ID=DPVDSDBID,Number=.,Type=String,Description="Variant disease database ID">
##INFO=<ID=DPVDBN,Number=.,Type=String,Description="Variant disease name">
##INFO=<ID=DPVHGVS,Number=.,Type=String,Description="Variant in HGVS.">
#CHROM	POS	ID	REF	ALT	QUAL	FILTER	INFO
1	243613681	NC_000001.10:g.243776983T>C	T	C	.	.	dbSNP_RSID=rs397514605;CLNALLELEID=48414;CLNDN=Megalencephaly-capillary_malformation-polymicrogyria_syndrome|Megalencephaly-polymicrogyria-polydactyly-hydrocephalus_syndrome_2;CLNDISDB=MONDO:MONDO:0011240,MedGen:C1865285,OMIM:602501,Orphanet:ORPHA60040|MONDO:MONDO:0014407,MedGen:C4014738,OMIM:615937;CLNSIG=Pathogenic;CLNHGVS=NC_000001.11:g.243613681T>C;GENEINFO=393:10000;DPVID=381;DPVSIG=Pathogenic;DPVDSDBID=OMIM:615937;DPVDBN=Megalencephaly-polymicrogyria-polydactyly-hydrocephalus_syndrome_2;DPVHGVS=NC_000001.11:g.243613681T>C	.