ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.781A>G (p.Asn261Asp) (rs781179797)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000725747 SCV000241849 uncertain significance not provided 2015-03-19 criteria provided, single submitter clinical testing The N294D 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 6,500 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 N294D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter 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).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725747 SCV000339131 uncertain significance not provided 2016-02-15 criteria provided, single submitter clinical testing
Invitae RCV000457101 SCV000552200 uncertain significance Pitt-Hopkins-like syndrome 2 2016-11-08 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 294 of the NRXN1 protein (p.Asn294Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs781179797, ExAC 0.006%) but has not been reported in the literature in individuals with a NRXN1-related disease. ClinVar contains an entry for this variant (Variation ID: 206211). 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. In summary, this variant is a rare missense change that is not predicted to affect 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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