ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs200604893
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Total submissions: 5
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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 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1453 of the NRXN1 protein (p.Gly1453Ser). This variant is present in population databases (rs200604893, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of NRXN1-related conditions (PMID: 22504536, 36703223). This variant is also known as c.1132G>A (p.Gly378Ser). ClinVar contains an entry for this variant (Variation ID: 206273). 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.
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital RCV002478658 SCV002775009 uncertain significance not provided 2022-12-17 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002478659 SCV002778836 uncertain significance Pitt-Hopkins-like syndrome 2; Chromosome 2p16.3 deletion syndrome 2021-11-16 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000534805 SCV003814154 uncertain significance Pitt-Hopkins-like syndrome 2 2019-05-29 criteria provided, single submitter clinical testing

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