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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16636593, 24836714, 21902834, 19219621, 24926462, 26051471, 29505567, 14564077, 14564066, 23079138, 9097956, 29460029, 30682568, 31102713)
ClinVar Genomic variation as it relates to human health
NM_000444.6(PHEX):c.1645C>T (p.Arg549Ter)
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.
(7)
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
7
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.1645C>T (p.Arg549Ter)
Variation ID: 279870 Accession: VCV000279870.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xp22.11 X: 22190502 (GRCh38) [ NCBI UCSC ] X: 22208619 (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 May 12, 2024 Jan 13, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000444.6:c.1645C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000435.3:p.Arg549Ter nonsense NM_001282754.2:c.1645C>T NP_001269683.1:p.Arg549Ter nonsense NC_000023.11:g.22190502C>T NC_000023.10:g.22208619C>T NG_007563.2:g.162699C>T - Protein change
- R549*
- Other names
- -
- Canonical SPDI
- NC_000023.11:22190501: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.
- -
- 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 | 1514 | |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 13, 2024 | RCV000280838.11 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 12, 2024 | RCV002250611.6 |
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
(May 02, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000614442.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
|
|
Pathogenic
(May 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329461.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16636593, 24836714, 21902834, 19219621, 24926462, 26051471, 29505567, 14564077, 14564066, 23079138, 9097956, 29460029, 30682568, 31102713) (less)
|
|
|
Pathogenic
(Jan 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001237314.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg549*) in the PHEX gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg549*) 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 individuals with hypophosphatemia (PMID: 9097956, 24836714, 29460029). ClinVar contains an entry for this variant (Variation ID: 279870). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial X-linked hypophosphatemic vitamin D refractory rickets
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002521064.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000279870 / PMID: 9097956). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Primary Fanconi syndrome (present)
|
|
|
Pathogenic
(Jul 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial X-linked hypophosphatemic vitamin D refractory rickets
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580948.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS4_MOD, PM2_SUP
|
Number of individuals with the variant: 1
Sex: male
|
|
|
Pathogenic
(May 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial X-linked hypophosphatemic vitamin D refractory rickets
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004013240.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PVS1, PS4
|
|
|
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: SCV004231765.2
First in ClinVar: Jan 26, 2024 Last updated: May 12, 2024 |
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg549*) 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 individuals with hypophosphatemia (PMID: 9097956, 24836714, 29460029). ClinVar contains an entry for this variant (Variation ID: 279870). For these reasons, this variant has been classified as Pathogenic.
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000279870 / PMID: 9097956). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PVS1, PS4
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:
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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16636593, 24836714, 21902834, 19219621, 24926462, 26051471, 29505567, 14564077, 14564066, 23079138, 9097956, 29460029, 30682568, 31102713)
Comment:
This sequence change creates a premature translational stop signal (p.Arg549*) 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 individuals with hypophosphatemia (PMID: 9097956, 24836714, 29460029). ClinVar contains an entry for this variant (Variation ID: 279870). For these reasons, this variant has been classified as Pathogenic.
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000279870 / PMID: 9097956). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
PVS1, PS4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations. | Chesher D | Journal of inherited metabolic disease | 2018 | PMID: 29460029 |
| RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
| Identification of two novel mutations in the PHEX gene in Chinese patients with hypophosphatemic rickets/osteomalacia. | Yue H | PloS one | 2014 | PMID: 24836714 |
| 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 |
| X-linked hypophosphatemia in Polish patients. 1. Mutations in the PHEX gene. | Popowska E | Journal of applied genetics | 2000 | PMID: 14564077 |
| Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets. | Holm IA | American journal of human genetics | 1997 | PMID: 9106524 |
| Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP). | Rowe PS | Human molecular genetics | 1997 | PMID: 9097956 |
Text-mined citations for rs886041224 ...
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 25, 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.