ClinVar Miner

Submissions for variant NM_001135659.2(NRXN1):c.821A>G (p.Asn274Ser) (rs759434607)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522827 SCV000616812 uncertain significance not provided 2017-09-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NRXN1 gene. The N274S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N274S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N274S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000700475 SCV000829232 uncertain significance Pitt-Hopkins-like syndrome 2 2018-02-27 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 274 of the NRXN1 protein (p.Asn274Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs759434607, 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: 449074). Algorithms developed to predict the effect of missense changes on protein structure and function output the following:PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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