ClinVar Miner

Submissions for variant NM_000397.4(CYBB):c.253-8A>G

dbSNP: rs1064793093
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485537 SCV000564922 uncertain significance not provided 2016-03-14 criteria provided, single submitter clinical testing The c.253-8 A>G variant has been published previously in association with chronic granulomatous disease (Rae et al., 1998). cDNA studies by Rae et al. indicate this variant causes a frameshift with termination in exon 4; however, no protein studies were performed. c.253-8 A>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Several in-silico splice prediction models predict that c.253-8 A>G creates a cryptic acceptor site which may supplant the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV001856812 SCV002296726 likely pathogenic Granulomatous disease, chronic, X-linked 2021-06-18 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the CYBB gene. It does not directly change the encoded amino acid sequence of the CYBB protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with chronic granulomatous disease (PMID: 9585602, 29560547, Invitae). ClinVar contains an entry for this variant (Variation ID: 418152). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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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