ClinVar Miner

Submissions for variant NM_001135659.2(NRXN1):c.2717T>C (p.Ile906Thr) (rs796052779)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188280 SCV000241891 uncertain significance not provided 2016-08-18 criteria provided, single submitter clinical testing The I906T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,000 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 I906T 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. 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. However, missense mutations in nearby residues have not been reported in association with epilepsy. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000538380 SCV000651817 uncertain significance Pitt-Hopkins-like syndrome 2 2017-03-22 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 906 of the NRXN1 protein (p.Ile906Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a NRXN1-related disease. ClinVar contains an entry for this variant (Variation ID: 206250). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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