ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.569A>G (p.Asn190Ser) (rs200792504)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000716587 SCV000847428 uncertain significance History of neurodevelopmental disorder 2017-09-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000515306 SCV000898865 uncertain significance Pitt-Hopkins-like syndrome 2; Schizophrenia 17 2018-07-03 criteria provided, single submitter clinical testing NRXN1 NM_001135659.2 exon 2 p.Asn190Ser (c.569A>G): This variant has not been reported in the literature but is present in 0.1% (130/120178) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs200792504). This variant is present in ClinVar (Variation ID:167390). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723758 SCV000203148 uncertain significance not provided 2014-01-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515306 SCV000611494 uncertain significance Pitt-Hopkins-like syndrome 2; Schizophrenia 17 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000188273 SCV000241883 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NRXN1 gene. The N190S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N190S variant is observed in 50/46,610 (0.1%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N190S 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. 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.
Genetic Services Laboratory, University of Chicago RCV000188273 SCV000248289 uncertain significance not specified 2015-07-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000305697 SCV000431216 uncertain significance Pitt-Hopkins-like syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000473936 SCV000552202 uncertain significance Pitt-Hopkins-like syndrome 2 2018-11-25 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 190 of the NRXN1 protein (p.Asn190Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs200792504, ExAC 0.1%). This variant has not been reported in the literature in individuals with NRXN1-related disease. ClinVar contains an entry for this variant (Variation ID: 167390). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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