ClinVar Miner

Submissions for variant NM_000444.6(PHEX):c.1900-1G>A

dbSNP: rs755406730
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000424080 SCV000536283 likely pathogenic not provided 2017-01-06 criteria provided, single submitter clinical testing The c.1900-1 G>A splice site variant in the PHEX gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant destroys the canonical splice acceptor site in intron 18; however, the adjacent exon 19 remains in-frame. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. Additionally, the variant 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. Therefore, we consider this variant to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000424080 SCV002232538 pathogenic not provided 2024-04-16 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 18 of the PHEX 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 PHEX are known to be pathogenic (PMID: 9097956, 9106524, 19219621). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with hypophosphatemic rickets (Invitae). ClinVar contains an entry for this variant (Variation ID: 392939). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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