Submissions for variant NM_001111125.3(IQSEC2):c.2889+1G>A

dbSNP: rs1556861311

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523673	SCV000621139	pathogenic	not provided	2017-09-27	criteria provided, single submitter	clinical testing	The c.2889+1G>A splice site variant in the IQSEC2 gene destroys the canonical splice donor site in intron 9. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that issubject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.2889+1G>A variant is not observed in large population cohorts (Lek et al., 2016). Although this pathogenic variant has not been previously reported to our knowledge, its presence is consistent with the diagnosis of an IQSEC2-related disorder in this individual.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000794238	SCV000933632	pathogenic	Intellectual disability, X-linked 1	2022-03-10	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 452339). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. Disruption of this splice site has been observed in individual(s) with clinical features of IQSEC2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This sequence change affects a donor splice site in intron 9 of the IQSEC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IQSEC2 are known to be pathogenic (PMID: 21686261, 26793055, 27665735). This variant is not present in population databases (gnomAD no frequency).