ClinVar Miner

Submissions for variant NM_000444.6(PHEX):c.1645+1G>A

dbSNP: rs886041225
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000336154 SCV000329462 pathogenic not provided 2024-02-01 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: 24857004, 19219621, 25525159, 24102521, 11502829, 30682568, 34434907, 33639975, 32329911, 33666701, 34141703, 36060934, 31102713, 10439971)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000505469 SCV000599641 pathogenic Familial X-linked hypophosphatemic vitamin D refractory rickets 2017-06-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000336154 SCV001212864 pathogenic not provided 2023-12-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 15 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 individuals with hypophosphatemic rickets (PMID: 10439971, 18625346, 19219621, 24857004; Invitae). ClinVar contains an entry for this variant (Variation ID: 279871). 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.
Illumina Laboratory Services, Illumina RCV000505469 SCV001451534 pathogenic Familial X-linked hypophosphatemic vitamin D refractory rickets 2019-03-16 criteria provided, single submitter clinical testing The PHEX c.1645+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. Across a selection of the available literature, the c.1645+1G>A variant has been identified in a heterozygous state in at least six individuals with a dominant form of X-linked hypophosphatemia, two of whom are related. The variant was proven to have arisen de novo in one individual (Filisetti et al. 1999; Holm et al. 2001; Ichikawa et al. 2008; Beck-Nielsen et al. 2012; Fahiminiya et al. 2014). Control data are unavailable for the c.1645+1G>A variant and is not found in the Genome Aggregation Database in a region of good sequencing coverage, so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the c.1645+1G>A variant is classified as pathogenic for X-linked hypophosphatemia.

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