Submissions for variant NM_000444.6(PHEX):c.2239C>T (p.Arg747Ter)

dbSNP: rs886041227

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000351204	SCV000329465	pathogenic	not provided	2022-01-14	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 3 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25894638, 24926462, 29505567, 9768674, 9199930, 26051471, 10439971, 11502829, 16055933, 21902834, 30607568, 30682568, 32253725, 32329911, 33666701, 34141703)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000505449	SCV000599629	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2013-10-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000351204	SCV000843046	pathogenic	not provided	2017-12-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000505449	SCV000893828	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000351204	SCV001374163	pathogenic	not provided	2023-05-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 279873). This premature translational stop signal has been observed in individuals with X-linked dominant hypophosphatemic rickets (PMID: 9199930, 9768674). 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 creates a premature translational stop signal (p.Arg747*) in the PHEX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acid(s) of the PHEX protein.
DASA	RCV002221523	SCV002499411	likely pathogenic	Autosomal dominant hypophosphatemic rickets	2022-04-10	criteria provided, single submitter	clinical testing	The c.2239C>T;p.(Arg747*) variant creates a premature translational stop signal in the PHEX gene without sufficient information about prediction of nonsense mediated mRNA decay (NMD) type change; it is present in a relevant exon to the transcript, and disrupts <10% of the protein product - PVS1_moderate.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 32329911)PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 279873; PMID: 21902834; 19219621; 16055933; 10439971) - PS4. This variant is not present in population databases (rs886041227- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br) - PM2. In summary, the currently available evidence indicates that the variant is likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000505449	SCV002767959	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2019-08-28	criteria provided, single submitter	clinical testing	A hemizygous nonsense variant was identified NM_000444.5(PHEX):c.2239C>T in exon 22 of 22 of the PHEX gene. This nonsense variant is predicted to create a change of arginine to a stop at amino acid position 747 of the protein, NP_000435.3(PHEX):p.(Arg747*), resulting in the loss of normal protein function through truncation. The variant is not present in the gnomAD population database. The variant has previously been reported as pathogenic and segregated with disease in multiple families with X-linked dominant hypophosphatemic rickets (ClinVar, Francis, F. et al. (1997), Holm, I. et al. (2001), Capelli, S. et al. (2015), Acar, S. et al. (2018)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000505449	SCV004231766	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2024-01-12	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000505449	SCV004814110	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets		criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000351204	SCV005197124	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing