ClinVar Miner

Submissions for variant NM_000444.6(PHEX):c.118+1G>A

dbSNP: rs1131691731
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001217335 SCV001389170 pathogenic not provided 2022-11-16 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 946464). Disruption of this splice site has been observed in individuals with hypophosphatemia (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003479295 SCV004223425 pathogenic Familial X-linked hypophosphatemic vitamin D refractory rickets 2023-11-07 criteria provided, single submitter clinical testing Variant summary: PHEX c.118+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the 5' canonical splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 182363 control chromosomes. c.118+1G>A has been reported in the literature in at-least three individuals affected with X-Linked Hypophosphatemic Rickets (examples, Baroncelli_2021, Lin_2021, Popowska_2001). These data indicate that the variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32772199, 34141703, 14564066). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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