ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.1978G>A (p.Ala660Thr) (rs199939303)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000718196 SCV000849058 uncertain significance History of neurodevelopmental disorder 2017-02-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000764444 SCV000895501 uncertain significance Pitt-Hopkins-like syndrome 2; Schizophrenia 17 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000188309 SCV000241920 uncertain significance not provided 2017-03-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NRXN1 gene. The A700T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A700T 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 A700T 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, and in silico analysis predicts this variant is probably damaging to 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 RCV000689938 SCV000817610 uncertain significance Pitt-Hopkins-like syndrome 2 2018-10-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 700 of the NRXN1 protein (p.Ala700Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs199939303, ExAC 0.01%). This variant has not been reported in the literature in individuals with NRXN1-related disease. ClinVar contains an entry for this variant (Variation ID: 206276). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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