Submissions for variant NM_001330078.2(NRXN1):c.2533C>T (p.His845Tyr)

gnomAD frequency: 0.00064  dbSNP: rs199784139

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000513409	SCV000241886	uncertain significance	not provided	2024-01-23	criteria provided, single submitter	clinical testing	Reported in a patient with autism spectrum disorder, sibling with learning disabilities and their unaffected father, and in an unrelated individual with spastic paraplegia and epilepsy who was also a compound heterozygote for 2 variants in the ALDH18A1 gene (PMID: 23849776, 29754261); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss-of-function; This variant is associated with the following publications: (PMID: 29754261, 34168285, 23849776)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465496	SCV000552204	likely benign	Pitt-Hopkins-like syndrome 2	2024-12-24	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000188275	SCV000596082	uncertain significance	not specified	2015-09-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000513409	SCV000608937	uncertain significance	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000513409	SCV000704629	uncertain significance	not provided	2016-12-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002314734	SCV000847536	uncertain significance	Inborn genetic diseases	2021-07-20	criteria provided, single submitter	clinical testing	The c.2653C>T (p.H885Y) alteration is located in exon 15 (coding exon 14) of the NRXN1 gene. This alteration results from a C to T substitution at nucleotide position 2653, causing the histidine (H) at amino acid position 885 to be replaced by a tyrosine (Y). The alteration is ultra rare in population databases:_x000D_ The NRXN1 c.2653C>T alteration was observed in 72 out of 120,252 total alleles studied (0.06%) in the Exome Aggregation Consortium (ExAC) database, with a frequency of 69/66,496 (0.1%) in the European (Non-Finnish) sub-population. Based on data from the NHLBI Exome Sequencing Project (ESP), the NRXN1 c.2653C>T alteration was observed in 12 among 12,074 total alleles studied (0.1%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. Rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012; please note that some variants may appear to be rare due to ethnic underrepresentation in the database)._x000D_ IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The alteration has been observed in affected individuals: _x000D_ The NRXN1 c.2653C>T (p.H885Y) alteration has been reported in a proband with autism spectrum disorder and his brother with a learning disability. The alteration was found to be inherited from the brothers' unaffected father (Jiang, 2013). The altered amino acid is conserved throughout evolution:_x000D_ The p.H885 amino acid is conserved in available vertebrate species. In silico prediction is conflicting:_x000D_ The p.H885Y alteration is predicted to be probably damaging by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000764442	SCV000895499	uncertain significance	Pitt-Hopkins-like syndrome 2; Chromosome 2p16.3 deletion syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000465496	SCV001302024	uncertain significance	Pitt-Hopkins-like syndrome 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV000465496	SCV001529580	uncertain significance	Pitt-Hopkins-like syndrome 2	2018-06-28	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000764442	SCV002495880	uncertain significance	Pitt-Hopkins-like syndrome 2; Chromosome 2p16.3 deletion syndrome	2021-03-30	criteria provided, single submitter	clinical testing	NRXN1 NM_001135659.2 exon 15 p.His885Tyr (c.2653C>T): This variant has been reported in the literature in at least 1 individual with autism spectrum disorder (ASD), segregating with disease in 1 affected family member. However, this family member did not meet clinical criteria for ASD (Jiang 2013 PMID:23849776). This variant is present in 0.1% (78/68024) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-50497679-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:20245). Evolutionary conservation suggests that this variant may impact the protein; 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000513409	SCV002541828	uncertain significance	not provided	2021-05-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000465496	SCV003814163	uncertain significance	Pitt-Hopkins-like syndrome 2	2021-06-11	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000513409	SCV001963022	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513409	SCV001966872	uncertain significance	not provided		no assertion criteria provided	clinical testing
GenomeConnect-Association for Creatine Deficiencies, Association for Creatine Deficiencies	RCV000764442	SCV002047665	not provided	Pitt-Hopkins-like syndrome 2; Chromosome 2p16.3 deletion syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 07-13-2019 by lab or GTR ID 26957. GenomeConnect - Association for Creatine Deficiencies assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.