ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs771759988
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Total submissions: 4
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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 ( This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD ( Variants that disrupt the consensus splice acceptor site in NRXN1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.

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