Submissions for variant NM_181523.3(PIK3R1):c.1425+1G>A

dbSNP: rs587777709

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413301	SCV000490721	pathogenic	not provided	2016-12-07	criteria provided, single submitter	clinical testing	The c.1425+1G>A pathogenic variant has been reported previously in association with PASLI disease (Lucas et al., 2014). cDNA studies indicated that c.1425+1G>A results in the skipping of exon 11 (Lucas et al., 2014). This splice site variant destroys the canonical splice donor site in intron 11. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1425+1G>A variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret this variant to be pathogenic.
Invitae	RCV000705809	SCV000834824	pathogenic	SHORT syndrome; Agammaglobulinemia 7, autosomal recessive; Immunodeficiency 36	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 11 of the PIK3R1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hypogammaglobulinemia with elevated IgM, activated PI3K-delta syndrome, and SHORT syndrome (PMID: 25488983, 25939554, 27076228, 27116393, 27693481, 28302518). In at least one individual the variant was observed to be de novo. This variant is also known as g.67589663G>A. ClinVar contains an entry for this variant (Variation ID: 372467). Studies have shown that disruption of this splice site results in skipping of exon 11, but is expected to preserve the integrity of the reading-frame (PMID: 27076228). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000413301	SCV000928008	pathogenic	not provided	2018-10-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000987525	SCV001136838	likely pathogenic	SHORT syndrome	2019-05-28	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001027613	SCV001190185	pathogenic	Inherited Immunodeficiency Diseases	2019-01-01	criteria provided, single submitter	research
Ambry Genetics	RCV001266930	SCV001445111	pathogenic	Inborn genetic diseases	2017-12-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000987525	SCV001520009	pathogenic	SHORT syndrome	2020-02-21	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
CeGaT Center for Human Genetics Tuebingen	RCV000413301	SCV001961884	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	PIK3R1: PM6:Strong, PM2, PS4:Moderate, PP3, PS3:Supporting
Fulgent Genetics, Fulgent Genetics	RCV000705809	SCV002813280	pathogenic	SHORT syndrome; Agammaglobulinemia 7, autosomal recessive; Immunodeficiency 36	2022-03-29	criteria provided, single submitter	clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156092	SCV003845300	pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003922673	SCV004744308	pathogenic	PIK3R1-related condition	2024-01-11	criteria provided, single submitter	clinical testing	The PIK3R1 c.1425+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported as a recurrent de novo mutation in multiple individuals with activated phosphoinositide 3-kinase δ syndrome type 2 (APDS2) (Lucas et al. 2014. PubMed ID: 25488983; Lougaris et al. 2015. PubMed ID: 25939554; Petrovski et al. 2016. PubMed ID: 27076228; Olbrich et al. 2016. PubMed ID: 27116393; Elkaim et al. 2016. PubMed ID: 27221134; Yazdani et al. 2019. PubMed ID: 30799802). RNA analysis has shown that this variant leads to an in-frame deletion of 42 amino acid residues, and in vitro functional studies using tranformed patient B cells have shown that this deletion leads to reduced p85α protein expression, constitutive activation of the PI3K complex, and upregulation of downstream AKT and mTOR signaling pathways (Petrovski et al. 2016. PubMed ID: 27076228). This variant has not been reported in a large population database, indicating this variant is rare. Several additional variants that disrupt the same splice donor site (c.1425+1G>C/T, +2T>A/G, +2_+3delTG, etc.) have been reported in multiple individuals with ADPS-related phenotypes (Deau et al. 2014. PubMed ID: 25133428; Elkaim et al. 2016. PubMed ID: 27221134). Variants that disrupt the consensus splice donor site in PIK3R1 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000515768	SCV000611865	pathogenic	Immunodeficiency 36	2023-03-15	no assertion criteria provided	literature only
MutSpliceDB: a database of splice sites variants effects on splicing, NIH	RCV000413301	SCV002106363	not provided	not provided		no assertion provided	research