ClinVar Genomic variation as it relates to human health
NM_000444.6(PHEX):c.1601C>T (p.Pro534Leu)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000444.6(PHEX):c.1601C>T (p.Pro534Leu)
Variation ID: 280076 Accession: VCV000280076.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp22.11 X: 22190458 (GRCh38) [ NCBI UCSC ] X: 22208575 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Feb 14, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000444.6:c.1601C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000435.3:p.Pro534Leu missense NM_001282754.2:c.1601C>T NP_001269683.1:p.Pro534Leu missense NC_000023.11:g.22190458C>T NC_000023.10:g.22208575C>T NG_007563.2:g.162655C>T P78562:p.Pro534Leu - Protein change
- P534L
- Other names
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- Canonical SPDI
- NC_000023.11:22190457:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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PHEX | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
853 | 1508 |
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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 21, 2024 | RCV000260839.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 28, 2019 | RCV000505461.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 7, 2022 | RCV001843504.3 |
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. |
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Pathogenic
(Nov 19, 2013)
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criteria provided, single submitter
Method: clinical testing
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Familial X-linked hypophosphatemic vitamin D refractory rickets
(X-linked inheritance)
Affected status: yes
Allele origin:
paternal,
germline,
maternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000599609.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Observation 1:
Sex: female
Tissue: blood
Observation 2:
Sex: female
Tissue: blood
Observation 3:
Sex: male
Tissue: blood
Observation 4:
Sex: female
Tissue: blood
Observation 5:
Sex: male
Tissue: blood
Observation 6:
Sex: female
Tissue: blood
Observation 7:
Sex: female
Tissue: blood
Observation 8:
Sex: female
Tissue: blood
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Pathogenic
(Mar 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329878.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24660072, 11502829, 20688626, 30298486, 22261628, 16055933, 29707405, 29460029, 25042154, 10439971, 14564077, 16636593, 21050253, 9768674, 19219621, 22101457, 22713460, 9097956, 9199930, 22695891, 18162710, 30599486, 30682568, 32104046, 32253725, 29505567, 34434907, 33639975, 32329911, 34141703, 27535533) (less)
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial X-linked hypophosphatemic vitamin D refractory rickets
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001141539.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Mar 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypophosphatemic rickets
Affected status: yes
Allele origin:
germline
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Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi
Accession: SCV002102783.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022
Comment:
p.(Pro534Leu); missense variant
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Number of individuals with the variant: 4
Age: 1-45 years
Sex: mixed
Geographic origin: India
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Pathogenic
(Jan 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001206281.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 534 of the PHEX protein (p.Pro534Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 534 of the PHEX protein (p.Pro534Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PHEX-related conditions (PMID: 9097956, 18162710, 19219621, 22261628, 29460029, 29505567). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 280076). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PHEX protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genetic and clinical profile of patients with hypophosphatemic rickets. | Marik B | European journal of medical genetics | 2022 | PMID: 35738466 |
Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia: Novel Mutations in PHEX and SLC34A3. | Acar S | PloS one | 2018 | PMID: 29505567 |
Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations. | Chesher D | Journal of inherited metabolic disease | 2018 | PMID: 29460029 |
Paravertebral ligament ossification in vitamin D-resistant rickets: incidence, clinical significance, and genetic evaluation. | Lee SH | Spine | 2012 | PMID: 22261628 |
PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets. | Gaucher C | Human genetics | 2009 | PMID: 19219621 |
PHEX gene mutations and genotype-phenotype analysis of Korean patients with hypophosphatemic rickets. | Song HR | Journal of Korean medical science | 2007 | PMID: 18162710 |
Genomic organization of the human PEX gene mutated in X-linked dominant hypophosphatemic rickets. | Francis F | Genome research | 1997 | PMID: 9199930 |
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 rs886041363 ...
HelpRecord last updated Sep 29, 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.