Submissions for variant NM_000444.6(PHEX):c.591A>G (p.Gln197=)

dbSNP: rs1556020818

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000505462	SCV000599678	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2013-11-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000505462	SCV001141517	likely pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001051990	SCV001216175	pathogenic	not provided	2023-02-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 29393334). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 438544). This variant has been observed in individual(s) with hypophosphatemic rickets (PMID: 21902834, 29393334, 30682568). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 197 of the PHEX mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PHEX protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
Revvity Omics, Revvity	RCV000505462	SCV002018776	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2022-03-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505462	SCV005726061	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2024-11-21	criteria provided, single submitter	clinical testing	Variant summary: PHEX c.591A>G alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5' donor site. Two predict the variant creates a 3' acceptor site. Three predict the variant abolishes a cryptic 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing in patient samples (example, Cao_2022, Liao_2018) by deleting 77 bp from the 3' end of exon 5, resulting in a predicted frameshift (example, Cao_2022, Liao_2018). mRNA expression data from patient samples indicated female carriers have approximately half PHEX mRNA levels of wild type controls, suggesting nonsense mediated decay (Liao_2018), but results in male hemizygous sample(s) were unclear. The variant was absent in 183360 control chromosomes. c.591A>G has been reported in the literature in the heterozygous or hemizygous state in multiple related individuals affected with X-Linked Hypophosphatemic Rickets (example, Cao_2022, Liao_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35842615, 29393334). ClinVar contains an entry for this variant (Variation ID: 438544). Based on the evidence outlined above, the variant was classified as pathogenic.