ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.3616A>G (p.Ile1206Val)

gnomAD frequency: 0.00002  dbSNP: rs751778015
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000193549 SCV000248284 uncertain significance not specified 2014-09-10 criteria provided, single submitter clinical testing
GeneDx RCV000767067 SCV000617000 uncertain significance not provided 2018-04-09 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NRXN1 gene. The I1246V 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 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The I1246V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV002517107 SCV003501265 uncertain significance Pitt-Hopkins-like syndrome 2 2022-01-25 criteria provided, single submitter clinical testing 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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 211691). This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. This variant is present in population databases (rs751778015, gnomAD 0.004%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1246 of the NRXN1 protein (p.Ile1246Val).

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