Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000484825 | SCV000573698 | uncertain significance | not provided | 2017-02-28 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the NRXN1 gene. The S1378A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S1378A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S1378A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. However, 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 variant or a rare benign variant. |
| Labcorp Genetics |
RCV003619683 | SCV004422628 | uncertain significance | Pitt-Hopkins-like syndrome 2 | 2023-03-01 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 423934). This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1378 of the NRXN1 protein (p.Ser1378Ala). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NRXN1 protein function. 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. |