ClinVar Miner

Submissions for variant NM_001111125.3(IQSEC2):c.2983C>T (p.Arg995Trp) (rs1057521657)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000425290 SCV000523952 pathogenic not provided 2018-03-08 criteria provided, single submitter clinical testing The R995W variant in the IQSEC2 gene has been reported previously as de novo, in the heterozygous state, in a female with intellectual disability, speech regression, and hypotonia (Srivastava et al., 2018). The R995W variant is not observed in large population cohorts (Lek et al., 2016). The R995W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R995W as a pathogenic variant
Invitae RCV001048074 SCV001212063 likely pathogenic Mental retardation, X-linked 1 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 995 of the IQSEC2 protein (p.Arg995Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with global developmental delay, hypotonia, and language regression (PMID: 29322350). ClinVar contains an entry for this variant (Variation ID: 383534). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.