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: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000310309 SCV000933940 likely pathogenic Pitt-Hopkins-like syndrome 2 2024-07-19 criteria provided, single submitter clinical testing 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). This variant is present in population databases (rs771759988, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with clinical features of NRXN1-related conditions (PMID: 26185613, 33004838, 36368308). This variant is also known as g.51253608C>T. ClinVar contains an entry for this variant (Variation ID: 336552). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
GeneDx RCV001753801 SCV002006373 uncertain significance not provided 2024-11-12 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, 36368308)
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.

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