ClinVar Miner

Submissions for variant NM_001330078.2(NRXN1):c.772+1032G>A (rs771759988)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,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 2018-12-03 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 and likely results in an absent or disrupted protein product. This variant is present in population databases (rs771759988, ExAC 0.02%). This variant has been reported in the literature within a cohort of individuals with autism spectrum disorders (PMID: 26185613). This variant is also known as g.51253608C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 336552). Donor and acceptor splice site variants 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, 25149956). 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.

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