rs587776934

Positions:

• chr19-18162974-G-A
• chr19-18162974-G-C
• chr19-18162974-G-T

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PS2_Moderate PM1_Supporting PS4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1117G>A (NM_005027.4) variant in PIK3R2 is a missense variant predicted to cause substitution of (p.Gly373Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides within the PIK3R2 SH2, sequence homology 2 domain of PIK3R2 that is defined as a critical functional domain by the ClinGen BMEP (PMID:26860062) (PM1_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; identified in 2 individuals with macrocephaly (>=2 SD) and Developmental Delay or Intellectual disability with cortical malformation, 13 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), it has been shown to significantly increase phosphorylation levels in patient cell lines (PMID:22729224), and has been identified in over 15 tumor samples in the literature and COSMIC (PMID:28086757,22729224, 28502725)). This variant has been identified as a de novo occurrence with confirmed parental relationships (PS2_moderate; PMID:22729224). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PM1_P, PS4_VS, PS2_M; 13 points (VCEP specifications version 1; Approved: 1/31/2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA130573/MONDO:0016054/018

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIK3R2 NM_005027.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:26 O:1
• Conservation: PhyloP100: 9.76

Genes affected

PIK3R2 (HGNC:8980): (phosphoinositide-3-kinase regulatory subunit 2) Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates phosphatidylinositol and similar compounds, creating second messengers important in growth signaling pathways. PI3K functions as a heterodimer of a regulatory and a catalytic subunit. The protein encoded by this gene is a regulatory component of PI3K. Three transcript variants, one protein coding and the other two non-protein coding, have been found for this gene. [provided by RefSeq, Apr 2019]

ENSG00000268173 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 8 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIK3R2	NM_005027.4	c.1117G>A	p.Gly373Arg	missense_variant	10/16	ENST00000222254.13	NP_005018.2
PIK3R2	NR_073517.2	n.1672G>A		non_coding_transcript_exon_variant	10/16
PIK3R2	NR_162071.1	n.1455G>A		non_coding_transcript_exon_variant	9/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIK3R2	ENST00000222254.13	c.1117G>A	p.Gly373Arg	missense_variant	10/16	1	NM_005027.4	ENSP00000222254.6
ENSG00000268173	ENST00000593731.1	n.1117G>A		non_coding_transcript_exon_variant	10/25	2		ENSP00000471914.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461378 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 Pathogenic:15 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	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 1 (MIM#603387). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0254 - This variant is suspected mosaic. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant with conflicting in silico predictions and very highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated SH2 domain (PDB, NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (ClinVar). Most of these individuals had de novo variants and were either heterozygous or mosaic for the variant (PMID: 22729224, 26520804, 28502725). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Analysis of proband lymphoblastoid cells found the variant resulted in elevated PIP3 levels (PMID: 22729224). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 24, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo or mosaic in at least two similarly affected unrelated individuals (PMID:22729224,26520804; 28502725, PS2, PS4_M). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.631, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Sep 07, 2018	[ACMG/AMP: PS2, PS3, PM1, PM2, PS4_moderate, PP1, PP3]; A de novo mosaic variant [PS2] within the PIK3R2 gene was detected and confirmed by sanger sequencing. This is a well-described pathogenic alteration associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome (PMID: 27854409) [PS4_moderate]. This variant has been reported to increase PI3K activity in vitro in a lymphoblastoid cell line derived from a patient with this alteration (PMID: 22729224), is absent from large-scale population databases, including gnomAD, and predicated to have a deleterious effect based on in silico modeling [PS3, PM2, PP3]. Mosaicism is the setting of PIK3R2-associated MPPH has been previously documented (PMID: 26520804; 28502725). Of note, autosomal dominant (vertical) transmission of this variant has been described among affected individuals in one pedigree [PP1], and additionally, gonadal mosaicism has been documented (PMID: 26520804; 27854409). -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. -
Likely pathogenic, no assertion criteria provided	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 10, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects PIK3R2 function (PMID: 22729224). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIK3R2 protein function. ClinVar contains an entry for this variant (Variation ID: 39808). This missense change has been observed in individual(s) with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, or clinical features of this syndrome (PMID: 22729224, 24497998, 26520804, 28086757). 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 glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 373 of the PIK3R2 protein (p.Gly373Arg). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 11, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2022	Published functional studies demonstrate that G373R results in increased PI3K activity (Riviere et al., 2012); 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; This variant is associated with the following publications: (PMID: 27117832, 23619167, 21984976, 22729224, 24816253, 25056374, 25344691, 24497998, 23592320, 26520804, 26860062, 23745724, 23449172, 30293990, 29051493, 28566443, 28086757, 32371413, 34018286, 33144663, 34170046, 33644862, 33726816, 33604570, 33100332, 27535533) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	PIK3R2: PS2:Very Strong, PM1, PM2, PS4:Moderate, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 08, 2020	DNA sequence analysis of the PIK3R2 gene demonstrated a sequence change, c.1117G>A, in exon 10 that results in an amino acid change, p.Gly373Arg. This sequence change is absent from the large population databases such as ExAC and gnomAD (dbSNP rs587776934). This sequence change has previously been described in several patients in de novo state with megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome (PMID: 22729224, 24497998, 26520804, 28086757 and 26860062). Clinical variability and germline mosaicism has also been reported with this variant in some families (PMIDs: 24497998, 22729224). Functional studies have reported that this variant results in an increased PI3K activity and elevated PI3K-mTOR signaling with possible impact on PIK3R2 protein function (PMID: 22729224). The p.Gly373Arg change affects a highly conserved amino acid residue located in a domain of the PIK3R2 protein that is known to be functional. The p.Gly373Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). These collective evidences indicate that this sequence change is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Brain Malformations Variant Curation Expert Panel

Feb 17, 2022

The c.1117G>A (NM_005027.4) variant in PIK3R2 is a missense variant predicted to cause substitution of (p.Gly373Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides within the PIK3R2 SH2, sequence homology 2 domain of PIK3R2 that is defined as a critical functional domain by the ClinGen BMEP (PMID: 26860062) (PM1_Supporting). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_VS; identified in 2 individuals with macrocephaly (>=2 SD) and Developmental Delay or Intellectual disability with cortical malformation, 13 individuals with a clinical diagnosis of megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome; (MPPH) or megalencephaly-capillary malformation-polymicrogyria syndrome; (MCAP), it has been shown to significantly increase phosphorylation levels in patient cell lines (PMID: 22729224), and has been identified in over 15 tumor samples in the literature and COSMIC (PMID: 28086757,22729224, 28502725)). This variant has been identified as a de novo occurrence with confirmed parental relationships (PS2_moderate; PMID: 22729224). In summary, this variant meets the criteria to be classified as Pathogenic for mosaic autosomal dominant overgrowth with or without cerebral malformations due to abnormalities in MTOR-pathway genes based on the ACMG/AMP criteria applied, as specified by the ClinGen Brain Malformations Expert Panel: PM2_P, PM1_P, PS4_VS, PS2_M; 13 points (VCEP specifications version 1; Approved: 1/31/2021) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2014

- -

PIK3R2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2024

The PIK3R2 c.1117G>A variant is predicted to result in the amino acid substitution p.Gly373Arg. This is the most frequently documented pathogenic variant in PIK3R2. It has been reported with de novo occurrence (constitutional and mosaic) in more than twenty patients with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome or related phenotypes (see for example, Rivière et al. 2012. PubMed ID: 22729224; Tapper et al. 2014. PubMed ID: 24497998; Mirzaa et al. 2015. PubMed ID: 26520804; Negishi et al. 2017. PubMed ID: 28086757). This variant has not been reported in a large population database, indicating it is rare. It is interpreted as pathogenic by the ClinGen Brain Malformations Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/39808/). This variant is interpreted as pathogenic. -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

-

- -

Seizure Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Apr 05, 2021

- -

Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department Of Pediatrics And Neonatology, Nagoya City University Graduate School Of Medical Sciences

Nov 01, 2015

The mutation was observed in 2 affected individuals of a macrocephaly. Patient, a 2 year-old boy, showed severe developmental delay, hypotonia, and dysmorphic facial features. He had no meaningful words. His last head circumference was 52.4 cm (+3.4SD). Patient, a 6 year-old boy, showed severe developmental delay, hypotonia, seizure, and dysmorphic facial features. He had no meaningful words. His last head circumference was 55.5 cm (+2.5SD). This mutation was confirmed de novo. The expression level of phosphorylated S6 ribosomal protein in their lymphoblastoid cell lines was elevated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;.
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.089	D
MutationAssessor	Uncertain	2.8	M;.;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.4	D;.;.
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.95
MutPred		0.69		Gain of MoRF binding (P = 0.0206);Gain of MoRF binding (P = 0.0206);Gain of MoRF binding (P = 0.0206);
MVP		0.84
MPC		2.1
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587776934; hg19: chr19-18273784; COSMIC: COSV55846573; COSMIC: COSV55846573;