ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.739C>G (p.Arg247Gly) (rs200009780)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188288 SCV000241899 uncertain significance not provided 2014-01-30 criteria provided, single submitter clinical testing The Arg247Gly missense change 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 variant is a non-conservative amino acid substitution of a positively charged Arginine residue with an uncharged, non-polar Glycine residue. It alters a position that is conserved in mammals but is not conserved in more distantly related species, and other missense mutations associated with epilepsy have not been reported in this region of the protein. In silico analysis predicts this variant likely has a benign effect on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Arg247Gly is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Invitae RCV000792500 SCV000931803 uncertain significance Pitt-Hopkins-like syndrome 2 2019-04-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 247 of the NRXN1 protein (p.Arg247Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs200009780, ExAC 0.2%). This variant has not been reported in the literature in individuals with NRXN1-related disease. ClinVar contains an entry for this variant (Variation ID: 206257). 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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