ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.1945A>G (p.Ile649Val) (rs200074974)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720360 SCV000851237 likely benign History of neurodevelopmental disorder 2017-12-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign) ,Sub-population frequency in support of benign classification (not ava blue, manual h-w)
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723794 SCV000203142 uncertain significance not provided 2015-09-01 criteria provided, single submitter clinical testing
GeneDx RCV000723794 SCV000241837 uncertain significance not provided 2018-06-22 criteria provided, single submitter clinical testing The I689V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I689V variant is observed in 156/126562 (0.1%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The I689V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Genetic Services Laboratory, University of Chicago RCV000188230 SCV000248276 uncertain significance not specified 2014-12-16 criteria provided, single submitter clinical testing
Invitae RCV000649744 SCV000771576 uncertain significance Pitt-Hopkins-like syndrome 2 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 689 of the NRXN1 protein (p.Ile689Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs200074974, ExAC 0.1%). This variant has not been reported in the literature in individuals with NRXN1-related disease. ClinVar contains an entry for this variant (Variation ID: 167387). 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, 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.

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