ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.76G>C (p.Glu26Gln)

gnomAD frequency: 0.00001  dbSNP: rs201847846
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498110 SCV000590228 uncertain significance not provided 2017-06-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NRXN1 gene. The E26Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E26Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E26Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. 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.
Invitae RCV001225086 SCV001397321 uncertain significance Pitt-Hopkins-like syndrome 2 2022-06-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 26 of the NRXN1 protein (p.Glu26Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 432495). 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. 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.
Ambry Genetics RCV003159608 SCV003910090 uncertain significance Inborn genetic diseases 2023-04-26 criteria provided, single submitter clinical testing The c.76G>C (p.E26Q) alteration is located in exon 2 (coding exon 1) of the NRXN1 gene. This alteration results from a G to C substitution at nucleotide position 76, causing the glutamic acid (E) at amino acid position 26 to be replaced by a glutamine (Q). Based on data from gnomAD, the C allele has an overall frequency of 0.0007% (1/152184) total alleles studied. The highest observed frequency was 0.001% (1/68030) of European (non-Finnish) alleles. This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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