Submissions for variant NM_000444.6(PHEX):c.871C>T (p.Arg291Ter)

dbSNP: rs866429868

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412793	SCV000490706	pathogenic	not provided	2022-03-18	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 9106524, 26040324, 23466123, 11004247, 27840894, 11502829, 29460029, 19219621, 9199930, 30607568, 30682568, 30298486, 29707405, 34434907, 33639975, 32329911, 34006472, 34141703, 33537138)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000505415	SCV000599608	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2015-04-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000505415	SCV000893826	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2018-10-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000412793	SCV001144931	pathogenic	not provided	2019-07-10	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412793	SCV001225097	pathogenic	not provided	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg291*) in the PHEX gene. It is expected to result in an absent or disrupted protein product. 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). This premature translational stop signal has been observed in individual(s) with hypophosphatemic rickets (PMID: 9106524, 11004247, 23466123, 26040324, 29460029, 30298486). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372454). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi	RCV001843518	SCV002102815	pathogenic	Hypophosphatemic rickets	2022-03-07	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000505415	SCV004231797	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2024-10-07	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000505415	SCV005900428	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2024-09-08	criteria provided, single submitter	clinical testing	This sequence change in PHEX is a nonsense variant predicted to create a premature stop codon, p.(Arg291*), in biologically relevant exon 8/22 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 22319799). Loss-of-function variants are a well-established cause of disease in exon 8 (ClinVar). This variant is absent from the population database gnomAD v4.1. This variant has been reported in multiple individuals with hypophosphataemia and segregates with hypophosphataemia in two unrelated families (PMID: 34633109, 11004247, 11502829). This variant has also been identified as a de novo occurrence with confirmed parental relationships in an individual and as a de novo occurrence with unconfirmed parental relationships in another individual with hypophosphataemic rickets (PMID: 36482408, 32329911). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PS4, PM2_Supporting, PM5_Supporting, PS2_Moderate/PM6
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	RCV000505415	SCV001482382	pathogenic	Familial X-linked hypophosphatemic vitamin D refractory rickets	2019-05-31	no assertion criteria provided	research