VCV000226119.10 - ClinVar

NM_000444.6(PHEX):c.1735G>A (p.Gly579Arg)

Interpretation:: Pathogenic/Likely pathogenic
Review status:: criteria provided, multiple submitters, no conflicts
Submissions:: 8
First in ClinVar:: May 21, 2016
Most recent Submission:: Feb 7, 2023
Last evaluated:: Oct 13, 2022
Accession:: VCV000226119.10
Variation ID:: 226119
Description:: single nucleotide variant

NM_000444.6(PHEX):c.1735G>A (p.Gly579Arg)

Allele ID

227925

Variant type

single nucleotide variant

Variant length

1 bp

Cytogenetic location

Xp22.11

Genomic location

X: 22219070 (GRCh38) GRCh38 UCSC

X: 22237187 (GRCh37) GRCh37 UCSC

HGVS

Nucleotide	Protein	Molecular consequence
NM_000444.6:c.1735G>A MANE Select	NP_000435.3:p.Gly579Arg	missense
NM_001282754.2:c.1735G>A	NP_001269683.1:p.Gly579Arg	missense
NC_000023.11:g.22219070G>A
NC_000023.10:g.22237187G>A
NG_007563.2:g.191267G>A
	P78562:p.Gly579Arg

... more HGVS ... less HGVS

Protein change

G579R

Other names

NM_000444.5(PHEX):c.1735G>A(p.Gly579Arg)

NM_001282754.1(PHEX):c.1735G>A(p.Gly579Arg)

Canonical SPDI

NC_000023.11:22219069:G:A

Functional consequence

Global minor allele frequency (GMAF)

Allele frequency

Links

ClinGen: CA10576256

UniProtKB: P78562#VAR_006745

dbSNP: rs875989883

VarSome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
Familial X-linked hypophosphatemic vitamin D refractory rickets	Pathogenic/Likely pathogenic	5	criteria provided, multiple submitters, no conflicts	Jan 3, 2022	RCV000211521.5
not provided	Pathogenic	2	criteria provided, multiple submitters, no conflicts	Oct 13, 2022	RCV000396672.6
Vitamin D-dependent rickets, type 2	Likely pathogenic	1	no assertion criteria provided	Apr 1, 2017	RCV000578203.1

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
PHEX		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	729	1329
PTCHD1-AS	-	-	-	GRCh38	2	521

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	More information
Likely pathogenic (Apr 05, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- Familial X-linked hypophosphatemic vitamin D refractory rickets Affected status: yes Allele origin: germline	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000268522.1 First in ClinVar: May 21, 2016 Last updated: May 21, 2016	Comment: The identified PHEX mutation is the likely genetic cause for the hypophosphatemic rickets observed in the patient. Age: 20-29 years Sex: female
Pathogenic (Oct 28, 2013)	criteria provided, single submitter (Classification criteria August 2017) 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, Klinikum rechts der Isar Accession: SCV000599652.1 First in ClinVar: May 21, 2016 Last updated: May 21, 2016	Publications: PubMed (2) PubMed: 9097956‚ 9199930 Observation 1: Zygosity: 1 Hemizygote Sex: male Tissue: blood Observation 2: Zygosity: 1 Single Heterozygote Sex: female Tissue: blood Observation 3: Zygosity: 1 Hemizygote Sex: male Tissue: blood Observation 4: Zygosity: 1 Hemizygote Sex: male Tissue: blood Observation 5: Zygosity: 1 Single Heterozygote Sex: female Tissue: blood Observation 6: Zygosity: 1 Single Heterozygote Sex: female Tissue: blood
Pathogenic (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	- Familial X-linked hypophosphatemic vitamin D refractory rickets Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803531.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018	Publications: PubMed (4) PubMed: 9199930‚ 11468271‚ 12727977‚ 24684036 Comment: This variant is interpreted as a Pathogenic, for Hypophosphatemic rickets, X-linked dominant, in X-linked Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple … (more) This variant is interpreted as a Pathogenic, for Hypophosphatemic rickets, X-linked dominant, in X-linked Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation found in unrelated patients. (PMID:9199930). PS3 => Well-established functional studies show a deleterious effect (PMID:11468271,12727977). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:24684036). (less)
Pathogenic (Sep 19, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	- Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329463.5 First in ClinVar: Dec 06, 2016 Last updated: Mar 08, 2017	Comment: The G579R missense variant in the PHEX gene has been reported previously as de novo and in association with X-linked hypophosphatemic rickets (Rowe et al., … (more) The G579R missense variant in the PHEX gene has been reported previously as de novo and in association with X-linked hypophosphatemic rickets (Rowe et al., 1997; Durmaz et al., 2013; Radlovic et al., 2014). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). G579R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, another nucelotide change at the same codon (c.1735 G>C) also leading to the G579R missense change, a missense variant in at the same residue (G579V), and missense variants in nearby residues (H580P, F582S, H584P) have all been reported in the Human Gene Mutation Database in association with PHEX-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Furthermore, functional studies of the G579R variant have shown that it results in incomplete glycosylation of the protein leading to failed expression at the plasma membrane and degradation within the endoplasmic reticulum (Sabbagh et al., 2001; Sabbagh et al., 2003). (less)
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- Familial X-linked hypophosphatemic vitamin D refractory rickets Affected status: yes Allele origin: germline	3billion Accession: SCV002058796.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:9199930 PMID:9199930 PMID:9097956 PMID:9097956 Comment: Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000226119,VCV000438542, PS1_S). The variant … (more) Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000226119,VCV000438542, PS1_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M).Different missense changes at the same codon (p.Gly579Val, p.Gly579Glu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372777,VCV000378359, PMID:9097956, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.931, 3CNET: 0.997, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Short stature (present) , Skeletal dysplasia (present) Zygosity: 1 Single Heterozygote
Pathogenic (Nov 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- Familial X-linked hypophosphatemic vitamin D refractory rickets Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002812640.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Oct 13, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	- not provided Affected status: unknown Allele origin: germline	Invitae Accession: SCV001217754.4 First in ClinVar: Apr 15, 2020 Last updated: Feb 07, 2023	Publications: PubMed (5) PubMed: 9097956‚ 9199930‚ 18625346‚ 29858904‚ 11468271 Comment: This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 579 of the PHEX protein (p.Gly579Arg). … (more) This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 579 of the PHEX protein (p.Gly579Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypophosphatemic rickets (PMID: 9097956, 9199930, 18625346, 29858904). ClinVar contains an entry for this variant (Variation ID: 226119). 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. Experimental studies have shown that this missense change affects PHEX function (PMID: 11468271). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Apr 01, 2017)	no assertion criteria provided Method: research	- Familial Hypophosphatemic Rickets Affected status: yes Allele origin: germline	Department of Traditional Chinese Medicine, Fujian Provincial Hospital Accession: SCV000680000.1 First in ClinVar: Feb 03, 2018 Last updated: Feb 03, 2018	Clinical Features: Hypomineralization of enamel (present) , Osteomalacia (present) , Elevated alkaline phosphatase (present) , Bowing of the legs (present) , Femoral bowing (present) , Hypophosphatemia (present) … (more) Hypomineralization of enamel (present) , Osteomalacia (present) , Elevated alkaline phosphatase (present) , Bowing of the legs (present) , Femoral bowing (present) , Hypophosphatemia (present) , Short stature (present) (less)

Comment:

This variant is interpreted as a Pathogenic, for Hypophosphatemic rickets, X-linked dominant, in X-linked Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation found in unrelated patients. (PMID:9199930). PS3 => Well-established functional studies show a deleterious effect (PMID:11468271,12727977). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:24684036).

Comment:

The G579R missense variant in the PHEX gene has been reported previously as de novo and in association with X-linked hypophosphatemic rickets (Rowe et al., 1997; Durmaz et al., 2013; Radlovic et al., 2014). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). G579R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, another nucelotide change at the same codon (c.1735 G>C) also leading to the G579R missense change, a missense variant in at the same residue (G579V), and missense variants in nearby residues (H580P, F582S, H584P) have all been reported in the Human Gene Mutation Database in association with PHEX-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Furthermore, functional studies of the G579R variant have shown that it results in incomplete glycosylation of the protein leading to failed expression at the plasma membrane and degradation within the endoplasmic reticulum (Sabbagh et al., 2001; Sabbagh et al., 2003).

Comment:

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000226119,VCV000438542, PS1_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M).Different missense changes at the same codon (p.Gly579Val, p.Gly579Glu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372777,VCV000378359, PMID:9097956, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.931, 3CNET: 0.997, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 579 of the PHEX protein (p.Gly579Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypophosphatemic rickets (PMID: 9097956, 9199930, 18625346, 29858904). ClinVar contains an entry for this variant (Variation ID: 226119). 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. Experimental studies have shown that this missense change affects PHEX function (PMID: 11468271). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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:

Citations for this variant

Title	Author	Journal	Year	Link
Genetic analysis of three families with X-linked dominant hypophosphatemic rickets.	Lin X	Journal of pediatric endocrinology & metabolism : JPEM	2018	PMID: 29858904
X-linked hypophosphatemic rickets: case report.	Radlović V	Srpski arhiv za celokupno lekarstvo	2014	PMID: 24684036
Mutational survey of the PHEX gene in patients with X-linked hypophosphatemic rickets.	Ichikawa S	Bone	2008	PMID: 18625346
Structure and function of disease-causing missense mutations in the PHEX gene.	Sabbagh Y	The Journal of clinical endocrinology and metabolism	2003	PMID: 12727977
Disease-causing missense mutations in the PHEX gene interfere with membrane targeting of the recombinant protein.	Sabbagh Y	Human molecular genetics	2001	PMID: 11468271
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
PMID:9097956	-	-	-	-
PMID:9199930	-	-	-	-

Text-mined citations for rs875989883...

These 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 Mar 18, 2023

ClinVar Genomic variation as it relates to human health

NM_000444.6(PHEX):c.1735G>A (p.Gly579Arg)

NM_000444.6(PHEX):c.1735G>A (p.Gly579Arg)

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs875989883...