ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.587C>T (p.Pro196Leu) (rs199836119)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188313 SCV000241924 uncertain significance not specified 2017-02-24 criteria provided, single submitter clinical testing The P196L 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 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution alters a position conserved in mammals in the predicted first Lamin G-like 1 domain in the extracellular region of the NRXN1 protein; however, no nearby missense mutations have been reported in association with NRXN1-related disorders. In addition, the P196L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. 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).
Illumina Clinical Services Laboratory,Illumina RCV000390375 SCV000431215 uncertain significance Pitt-Hopkins-like syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000815563 SCV000956024 uncertain significance Pitt-Hopkins-like syndrome 2 2018-08-08 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 196 of the NRXN1 protein (p.Pro196Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NRXN1-related disease. ClinVar contains an entry for this variant (Variation ID: 206279). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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