Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000508456 | SCV000604668 | pathogenic | not specified | 2017-01-26 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000623166 | SCV000740694 | pathogenic | Inborn genetic diseases | 2022-01-13 | criteria provided, single submitter | clinical testing | The c.1425+1G>C intronic variant results from a G to C substitution one nucleotide after exon 11 (coding exon 10) of the PIK3R1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with PIK3R1-related immunodeficiency (Deau, 2014; Lucas, 2014; Elkaim, 2016; Kuhlen, 2015). Another alteration impacting the same donor site (c.1425+1G>A) has been shown to have a similar impact on splicing (skipping of coding exon 10) in an individual with hyper IgM syndrome, lymphadenopathy, and short stature (Petrovski, 2016). This nucleotide position is highly conserved in available vertebrate species. RT-PCR sequencing showed that this alteration resulted in an in-frame deletion of coding exon 10 (Deau, 2014). Functional analysis demonstrated that the alteration abrogates inhibitory activity and promotes AKT activation resulting in a mutant p85αΔ434_475 that was observed to be less stable than the wild type protein (Deau, 2014). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. |
| Invitae | RCV000800719 | SCV000940449 | pathogenic | SHORT syndrome; Agammaglobulinemia 7, autosomal recessive; Immunodeficiency 36 | 2022-09-26 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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: 25133428, 25488983). ClinVar contains an entry for this variant (Variation ID: 156009). This variant is also known as g.67589663G>C. Disruption of this splice site has been observed in individual(s) with activated PI3K delta syndrome (APDS2) (PMID: 25133428, 25488983, 26529633). 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 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. |
| Center for Personalized Medicine, |
RCV003156075 | SCV003845239 | pathogenic | See cases | 2022-12-21 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000144066 | SCV000189138 | pathogenic | Immunodeficiency 36 | 1995-03-01 | no assertion criteria provided | literature only |