ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.374A>G (p.Asn125Ser) (rs770641207)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188267 SCV000241877 uncertain significance not provided 2018-03-20 criteria provided, single submitter clinical testing The Asn125Ser 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 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Asn125Ser alters a well conserved position in the Laminin G domain of the Neurexin-1 protein. However, the amino acid substitution is conservative as both Asparagine and Serine are uncharged, polar amino acid residues. In addition, several in-silico algorithms predict Asn125Ser may be benign. Therefore, based on the currently available information, it is unclear whether Asn125Ser is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000701447 SCV000830248 uncertain significance Pitt-Hopkins-like syndrome 2 2018-04-11 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 125 of the NRXN1 protein (p.Asn125Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs770641207, ExAC 0.02%). This variant has not been reported in the literature in individuals with NRXN1-related disease. ClinVar contains an entry for this variant (Variation ID: 206238). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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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