ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.4237G>A (p.Gly1413Ser) (rs200604893)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188306 SCV000241917 uncertain significance not specified 2014-10-06 criteria provided, single submitter clinical testing This variant p.Gly1453Ser alters both the alpha and beta transcripts of the NRXN1 protein. In the shorter beta-neurexin transcript (NM_128735.2), the variant is denoted p.G348S and has been published using alternative nomeclature (G378S) in a patient with autism, intellectual disability and compulsive personality disorder and his mother who had an unspecified mental disorder (Camacho-Garcia et al., 2012). In the primary transcript (NM_001135659.1) the variant is denoted p.G1453S. Regardless of the transcript, this variant is a non-conservative amino acid substitution that alters a position that is conserved in mammals. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and 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 mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Invitae RCV000534805 SCV000651831 uncertain significance Pitt-Hopkins-like syndrome 2 2019-10-14 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1453 of the NRXN1 protein (p.Gly1453Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs200604893, ExAC 0.02%). This variant has been reported in an individual affected with autism, profound mental retardation, and compulsive personality disorder and his mother who was reported to have a non-specified mental disorder (PMID: 2504536). ClinVar contains an entry for this variant (Variation ID: 206273). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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