Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000623458 | SCV000742942 | pathogenic | Inborn genetic diseases | 2018-10-02 | criteria provided, single submitter | clinical testing | The c.865-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 10 of the DDX3X gene. This variant has been determined to be the result of a de novo mutation or germline mosaicism in two families with an isolated case of developmental delay, intellectual disability, and/or hypootnia (Ambry internal data). Different de novo alterations at the same acceptor site (c.865-2A>G and c.865-1G>A) have also been reported in individuals with developmental delay and/or intellectual disability (Snijders Blok L et al. Am. J. Hum. Genet., 2015 Aug;97:343-52; Lelieveld SH et al. Nat. Neurosci., 2016 09;19:1194-6; Wang et al. Ann. Clin. Transl. Neurol. 2018). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. |
| Ce |
RCV001093495 | SCV001250515 | pathogenic | not provided | 2019-03-01 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV001093495 | SCV001875274 | pathogenic | not provided | 2022-06-08 | criteria provided, single submitter | clinical testing | Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26235985, 33993884, 32135084, 27535533) |
| Labcorp Genetics |
RCV001093495 | SCV002959794 | pathogenic | not provided | 2023-08-23 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 522074). Disruption of this splice site has been observed in individual(s) with X-linked intellectual disability (PMID: 32135084). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 9 of the DDX3X 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 DDX3X are known to be pathogenic (PMID: 26235985). |
| Clinical Genetics Laboratory, |
RCV001093495 | SCV005197702 | pathogenic | not provided | 2022-05-27 | criteria provided, single submitter | clinical testing |