Submissions for variant NM_001330078.2(NRXN1):c.569A>G (p.Asn190Ser)

gnomAD frequency: 0.00074  dbSNP: rs200792504

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723758	SCV000203148	uncertain significance	not provided	2014-01-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000723758	SCV000241883	likely benign	not provided	2021-01-06	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000188273	SCV000248289	uncertain significance	not specified	2015-07-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000473936	SCV000431216	uncertain significance	Pitt-Hopkins-like syndrome 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000473936	SCV000552202	uncertain significance	Pitt-Hopkins-like syndrome 2	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 190 of the NRXN1 protein (p.Asn190Ser). This variant is present in population databases (rs200792504, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 167390). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Fulgent Genetics, Fulgent Genetics	RCV000515306	SCV000611494	uncertain significance	Pitt-Hopkins-like syndrome 2; Chromosome 2p16.3 deletion syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002312998	SCV000847428	uncertain significance	Inborn genetic diseases	2020-09-17	criteria provided, single submitter	clinical testing	The p.N190S variant (also known as c.569A>G), located in coding exon 1 of the NRXN1 gene, results from an A to G substitution at nucleotide position 569. The asparagine at codon 190 is replaced by serine, an amino acid with highly similar properties. This variant was identified in three samples in a cohort of individuals with intellectual disability and congenital heart disease; however, detailed clinical information was not provided (Grozeva D et al. Hum. Mutat., 2015 Dec;36:1197-204). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000515306	SCV000898865	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 2 p.Asn190Ser (c.569A>G): This variant has not been reported in the literature but is present in 0.1% (130/120178) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs200792504). This variant is present in ClinVar (Variation ID:167390). Evolutionary conservation and 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	RCV000723758	SCV001713992	uncertain significance	not provided	2021-06-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000473936	SCV003814157	uncertain significance	Pitt-Hopkins-like syndrome 2	2019-03-13	criteria provided, single submitter	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001251857	SCV001427602	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing