Submissions for variant NM_001330078.2(NRXN1):c.772+1032G>A

gnomAD frequency: 0.00004  dbSNP: rs771759988

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000310309	SCV000431213	uncertain significance	Pitt-Hopkins-like syndrome 2	2017-04-27	criteria provided, single submitter	clinical testing	The NRXN1 c.773-1G>A variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found based on this search. The c.773-1G>A variant is reported at a frequency of 0.00024 in the East Asian population of the Exome Aggregation Consortium but this is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of splice acceptor variants and the lack of clarifying evidence, the c.773-1G>A variant is classified as a variant of unknown significance but suspicious for pathogenicity. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000310309	SCV000933940	likely pathogenic	Pitt-Hopkins-like syndrome 2	2023-03-12	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 336552). This variant is also known as g.51253608C>T. Disruption of this splice site has been observed in individual(s) with clinical features of NRXN1-related conditions (PMID: 26185613, 33004838). This variant is present in population databases (rs771759988, gnomAD 0.01%). This sequence change affects an acceptor splice site in intron 2 of the NRXN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NRXN1 are known to be pathogenic (PMID: 19896112, 21964664, 23495017, 23533028, 25149956, 30031152).
GeneDx	RCV001753801	SCV002006373	uncertain significance	not provided	2023-08-31	criteria provided, single submitter	clinical testing	Identified as heterozygous in large cohorts of individuals with neurodevelopmental disorders and epilepsy, however detailed clinical and segregation information was not provided (Truty et al., 2019; Wang et al., 2020); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26185613, 31440721, 33004838)
PreventionGenetics, part of Exact Sciences	RCV004530374	SCV004115645	likely pathogenic	NRXN1-related disorder	2022-12-15	criteria provided, single submitter	clinical testing	The NRXN1 c.773-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported as a rare loss of function variant in a study of individuals with autism spectrum disorder (Additional File 3, Griswold et al. 2015. PubMed ID: 26185613) and as a rare variant in individuals with neurodevelopmental disorders (Supplemental Dataset 5, Wang et al. 2020. PubMed ID: 33004838). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-51253608-C-T). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-51253608-C-T). Variants that disrupt the consensus splice acceptor site in NRXN1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.