ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.2036C>T (p.Pro679Leu) (rs201735573)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188257 SCV000241867 uncertain significance not specified 2017-06-27 criteria provided, single submitter clinical testing The Pro719Leu missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Pro719Leu in approximately 5,000 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Although Proline and Leucine are both uncharged non-polar amino acids, the loss of a bulky Proline residue may alter the secondary structure of the protein. Pro719Leu alters a highly conserved position in the second epidermal growth factor-like domain of the neurexin 1-alpha protein. However, this position is not conserved in related proteins and multiple in silico algorithms predict that Pro719Leu is not pathogenic. Therefore, based on the information currently available, it is unclear whether Pro719Leu is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Genetic Services Laboratory, University of Chicago RCV000188257 SCV000596084 uncertain significance not specified 2017-05-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000719891 SCV000850762 uncertain significance History of neurodevelopmental disorder 2019-08-21 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000799433 SCV000939095 uncertain significance Pitt-Hopkins-like syndrome 2 2019-07-19 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 719 of the NRXN1 protein (p.Pro719Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs201735573, ExAC 0.02%). This variant has not been reported in the literature in individuals with NRXN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 206228). 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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