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.
ClinVar Genomic variation as it relates to human health
NM_000444.6(PHEX):c.2239C>T (p.Arg747Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(10)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000444.6(PHEX):c.2239C>T (p.Arg747Ter)
Variation ID: 279873 Accession: VCV000279873.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xp22.11 X: 22247942 (GRCh38) [ NCBI UCSC ] X: 22266059 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 Aug 25, 2024 Jan 12, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000444.6:c.2239C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000435.3:p.Arg747Ter nonsense NM_001282754.2:c.*74C>T 3 prime UTR NC_000023.11:g.22247942C>T NC_000023.10:g.22266059C>T NG_007563.2:g.220139C>T - Protein change
- R747*
- Other names
- -
- Canonical SPDI
- NC_000023.11:22247941:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PHEX | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
858 | 1513 | |
| PTCHD1-AS | - | - | - | GRCh38 | 2 | 610 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
May 25, 2023 | RCV000351204.12 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 12, 2024 | RCV000505449.10 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 10, 2022 | RCV002221523.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 28, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Familial X-linked hypophosphatemic vitamin D refractory rickets
(X-linked inheritance)
Affected status: yes
Allele origin:
germline,
de novo
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000599629.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Observation 1:
Sex: male
Tissue: blood
Observation 2:
Sex: female
Tissue: blood
Observation 3:
Sex: male
Tissue: blood
Observation 4:
Sex: male
Tissue: blood
Observation 5:
Sex: male
Tissue: blood
Observation 6:
Sex: male
Tissue: blood
Observation 7:
Sex: female
Tissue: blood
|
|
|
Pathogenic
(Dec 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000843046.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial X-linked hypophosphatemic vitamin D refractory rickets
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893828.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Likely pathogenic
(Apr 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant hypophosphatemic rickets
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002499411.1
First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
|
|
|
Pathogenic
(Aug 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial X-linked hypophosphatemic vitamin D refractory rickets
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767959.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Jan 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329465.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(May 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001374163.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Familial X-linked hypophosphatemic vitamin D refractory rickets
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV004814110.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Sex: female
|
|
|
Pathogenic
(Jan 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial X-linked hypophosphatemic vitamin D refractory rickets
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004231766.2
First in ClinVar: Jan 26, 2024 Last updated: May 12, 2024 |
|
|
|
Pathogenic
(Jul 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197124.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
Comment:
Comment:
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.
Comment:
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)
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Functional Characterization of PHEX Gene Variants in Children With X-Linked Hypophosphatemic Rickets Shows No Evidence of Genotype-Phenotype Correlation. | Zheng B | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | 2020 | PMID: 32329911 |
| Genetic diagnosis of X-linked dominant Hypophosphatemic Rickets in a cohort study: tubular reabsorption of phosphate and 1,25(OH)2D serum levels are associated with PHEX mutation type. | Morey M | BMC medical genetics | 2011 | PMID: 21902834 |
| PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets. | Gaucher C | Human genetics | 2009 | PMID: 19219621 |
| A clinical and molecular genetic study of hypophosphatemic rickets in children. | Cho HY | Pediatric research | 2005 | PMID: 16055933 |
| X-linked hypophosphatemia in Polish patients. 2. Analysis of clinical features and genotype-phenotype correlation. | Popowska E | Journal of applied genetics | 2001 | PMID: 14564066 |
| X-linked hypophosphatemia in Polish patients. 1. Mutations in the PHEX gene. | Popowska E | Journal of applied genetics | 2000 | PMID: 14564077 |
| Non-random distribution of mutations in the PHEX gene, and under-detected missense mutations at non-conserved residues. | Filisetti D | European journal of human genetics : EJHG | 1999 | PMID: 10439971 |
| Mutational analysis of PHEX gene in X-linked hypophosphatemia. | Dixon PH | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9768674 |
| Genomic organization of the human PEX gene mutated in X-linked dominant hypophosphatemic rickets. | Francis F | Genome research | 1997 | PMID: 9199930 |
Text-mined citations for rs886041227 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.