ClinVar Miner

Submissions for variant NM_000444.6(PHEX):c.1587-1G>A (rs886041839)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000269158 SCV000330608 pathogenic not provided 2017-01-25 criteria provided, single submitter clinical testing The c.1587-1 G>A splice site variant in the PHEX gene destroys the canonical splice acceptor site in intron 14. 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. The c.1587-1 G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Another pathogenic variant at this nucleotide (c.1587-1 G>C) has been observed at GeneDx and published as a pathogenic variant in a patient diagnosed with hypophosphatemic rickets (Beck-Nielsen et al., 2012). Although this pathogenic variant has not been previously reported to our knowledge, its presence is consistent with the diagnosis of X-linked hypophosphatemic rickets.
Invitae RCV000269158 SCV001230528 pathogenic not provided 2019-11-18 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 14 of the PHEX gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in an individual affected with hypophosphatemic rickets (PMID: 22695891). ClinVar contains an entry for this variant (Variation ID: 280672). 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. Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV001169961 SCV001251670 pathogenic Familial X-linked hypophosphatemic vitamin D refractory rickets 2020-05-03 criteria provided, single submitter clinical testing

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