Submissions for variant NM_001111125.3(IQSEC2):c.2507C>T (p.Ala836Val)

dbSNP: rs782099475

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000428798	SCV000513290	pathogenic	not provided	2017-05-03	criteria provided, single submitter	clinical testing	The A836V variant in the IQSEC2 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has been observed in a few unrelated individuals with developmental delay/intellectual disability including confirmed de novo occurrences referred for testing at GeneDx. The A836V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. While, the A836V variant is a conservative amino acid substitution, this substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret A836V as a pathogenic variant.
Invitae	RCV000796578	SCV000936097	pathogenic	Intellectual disability, X-linked 1	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 836 of the IQSEC2 protein (p.Ala836Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability (PMID: 28815955, 30666632, 31415821; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 377978). 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 IQSEC2 protein function. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000428798	SCV001248227	pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000796578	SCV001423699	likely pathogenic	Intellectual disability, X-linked 1	2018-10-18	criteria provided, single submitter	clinical testing	[ACMG/AMP: PS2, PM2, PS4_Moderate, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], is predicted to be damaging by multiple functional prediction tools [PP3].