ClinVar Miner

Submissions for variant NM_000444.6(PHEX):c.1482+1G>A

dbSNP: rs1064793228
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482782 SCV000565371 likely pathogenic not provided 2018-06-28 criteria provided, single submitter clinical testing To our knowledge, the c.1482+1 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant. The c.1482+1 G>A splice site variant in the PHEX gene destroys the canonical splice donor site in intron 13 and is predicted to cause abnormal gene splicing. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, splice variants at the same nucleotide position (c.1482+1 G>T and c.1482+1 G>C) have been reported in patients with hypophosphatemic rickets (Durmaz et al., 2013; Dixon et al., 1998; Holm et al., 2001). Furthermore, other splice variants in intron 13 have been reported in the Human Gene Mutation Database in association with hypophosphatemic rickets (Stenson et al., 2014). In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Athena Diagnostics RCV000482782 SCV000843044 pathogenic not provided 2018-05-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000482782 SCV001580733 pathogenic not provided 2023-04-11 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 418407). Disruption of this splice site has been observed in individual(s) with hypophosphatemic rickets (PMID: 9768674, 11502829, 23079138; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 13 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).
3billion, Medical Genetics RCV002250634 SCV002521848 pathogenic Familial X-linked hypophosphatemic vitamin D refractory rickets 2022-05-22 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000418407). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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