Submissions for variant NM_001111125.3(IQSEC2):c.4039dup (p.Ala1347fs)

dbSNP: rs1064795512

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481040	SCV000571390	likely pathogenic	not provided	2016-08-25	criteria provided, single submitter	clinical testing	The c.4039dupG variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 2,280 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.4039dupG variant in the IQSEC2 gene causes a frameshift starting with codon Alanine 1347, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 40 of the new reading frame, denoted p.Ala1347GlyfsX40. The last 142 amino acids are replaced by 39 incorrect amino acids. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000697019	SCV000825609	pathogenic	Intellectual disability, X-linked 1	2023-06-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the IQSEC2 protein in which other variant(s) (p.Lys1480Argfs*17) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 422032). This premature translational stop signal has been observed in individual(s) with epileptic encephalopathy, microcephaly and autism spectrum disorder (PMID: 27864847). 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 creates a premature translational stop signal (p.Ala1347Glyfs*40) in the IQSEC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 142 amino acid(s) of the IQSEC2 protein.