ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.4220A>G (p.Asn1407Ser)

gnomAD frequency: 0.00001  dbSNP: rs146968018
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000688095 SCV000815694 uncertain significance Pitt-Hopkins-like syndrome 2 2023-12-08 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1447 of the NRXN1 protein (p.Asn1447Ser). This variant is present in population databases (rs146968018, gnomAD 0.003%). 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: 567894). 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 with a negative predictive value of 80%. 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.
GeneDx RCV001555116 SCV001776473 uncertain significance not provided 2020-09-25 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002331338 SCV002632177 uncertain significance Inborn genetic diseases 2022-09-29 criteria provided, single submitter clinical testing The c.4340A>G (p.N1447S) alteration is located in exon 24 (coding exon 23) of the NRXN1 gene. This alteration results from a A to G substitution at nucleotide position 4340, causing the asparagine (N) at amino acid position 1447 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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