Submissions for variant NM_001330078.2(NRXN1):c.2437C>T (p.Arg813Cys)

gnomAD frequency: 0.00007  dbSNP: rs201150987

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000649731	SCV000771563	uncertain significance	Pitt-Hopkins-like syndrome 2	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 853 of the NRXN1 protein (p.Arg853Cys). This variant is present in population databases (rs201150987, gnomAD 0.02%). This missense change has been observed in individual(s) with neurodevelopmental disorders (PMID: 21424692, 33004838). This variant is also known as R813C. ClinVar contains an entry for this variant (Variation ID: 539874). 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 disruptive. Experimental studies have shown that this missense change does not substantially affect NRXN1 function (PMID: 21424692). 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.
GeneDx	RCV001551717	SCV001772284	likely benign	not provided	2021-05-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21424692)
New York Genome Center	RCV000649731	SCV002025722	uncertain significance	Pitt-Hopkins-like syndrome 2	2020-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002531944	SCV003716342	uncertain significance	Inborn genetic diseases	2020-11-04	criteria provided, single submitter	clinical testing	The c.2557C>T (p.R853C) alteration is located in exon 14 (coding exon 13) of the NRXN1 gene. This alteration results from a C to T substitution at nucleotide position 2557, causing the arginine (R) at amino acid position 853 to be replaced by a cysteine (C). Based on data from the Genome Aggregation Database (gnomAD) database, the NRXN1 c.2557C>T alteration was observed in 0.01% (22/279786) of total alleles studied, with a frequency of 0.02% (21/127956) in the European (non-Finnish) subpopulation. This alteration has been reported heterozygous as c.2437C>T (p.R813C) once from a cohort of patients with nonsyndromic intellectual disability. Inheritance was not determined. This alteration was also reported heterozygous in a patient with global developmental delay, hypotonia, toe syndactyly, micrognathia, and dysmorphic features as well as in the patient's father who had delay, hearing abnormalities, and learning difficulties. However, the proband also had a 1.18 Mb duplication of unknown significance (Deciphering Developmental Disorders Study, 2015; Gauthier, 2011). This amino acid position is highly conserved in available vertebrate species. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000649731	SCV003814161	uncertain significance	Pitt-Hopkins-like syndrome 2	2021-12-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003420139	SCV004117244	uncertain significance	NRXN1-related condition	2023-05-12	criteria provided, single submitter	clinical testing	The NRXN1 c.2557C>T variant is predicted to result in the amino acid substitution p.Arg853Cys. Using an alternate transcript (NM_004801), this variant is also referred to in the literature as c.2437C>T (p.Arg813Cys aka R813C). This variant was reported in an individual with nonsyndromic intellectual disability (Supplementary Table 1, Gauthier et al. 2011. PubMed ID: 21424692). This variant was also identified in a large-scaler study analyzing risk genes for neurodevelopmental disorders, however limited data was provided (Supplementary Dataset 5, Wang et al. 2020. PubMed ID: 33004838). This variant was also identified in a Deciphering Developmental Disorders Study analyzing individuals with severe, undiagnosed, developmental disorders, however the variant was paternally inherited and the patient also carried a maternally inherited GLI2 variant (Supplementary Table 4, Deciphering Developmental Disorders Study. 2014. PubMed ID: 25533962). Of note, a functional study showed that this variant had similar function to that of controls (Gauthier et al. 2011. PubMed ID: 21424692). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-50733693-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.