ClinVar Miner

Submissions for variant NM_001111125.3(IQSEC2):c.2507C>T (p.Ala836Val) (rs782099475)

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Total submissions: 4
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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 uncertain significance Mental retardation, X-linked 1 2019-03-12 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 836 of the IQSEC2 protein (p.Ala836Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs782099475, ExAC 0.01%). This variant has been observed in individuals affected with intellectual disability (PMID: 28815955, Invitae). ClinVar contains an entry for this variant (Variation ID: 377978). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik 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 Mental retardation, 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].

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