NM_000444.6(PHEX):c.1368G>C (p.Trp456Cys) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 4, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000413461.12

Allele description [Variation Report for NM_000444.6(PHEX):c.1368G>C (p.Trp456Cys)]

NM_000444.6(PHEX):c.1368G>C (p.Trp456Cys)

Gene:

PHEX:phosphate regulating endopeptidase X-linked [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp22.11

Genomic location:

Preferred name:

NM_000444.6(PHEX):c.1368G>C (p.Trp456Cys)

HGVS:

NC_000023.11:g.22133588G>C
NG_007563.2:g.105785G>C
NM_000444.6:c.1368G>CMANE SELECT
NM_001282754.2:c.1368G>C
NP_000435.3:p.Trp456Cys
NP_001269683.1:p.Trp456Cys
NC_000023.10:g.22151705G>C
NM_000444.4:c.1368G>C
NM_000444.5:c.1368G>C

Protein change:

W456C

Links:

dbSNP: rs886043680

NCBI 1000 Genomes Browser:

rs886043680

Molecular consequence:

NM_000444.6:c.1368G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282754.2:c.1368G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000341459	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Jun 1, 2016)	germline	clinical testing	Citation Link,
SCV000491263	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Jul 19, 2016)	germline	clinical testing	Citation Link,
SCV001396645	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 4, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10439971, 22101457, 29460029, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000341459

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Uncertain significance
(Jun 1, 2016)

germline

clinical testing

Citation Link,

SCV000491263

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Jul 19, 2016)

germline

clinical testing

Citation Link,

SCV001396645

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 4, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Non-random distribution of mutations in the PHEX gene, and under-detected missense mutations at non-conserved residues.

Filisetti D, Ostermann G, von Bredow M, Strom T, Filler G, Ehrich J, Pannetier S, Garnier JM, Rowe P, Francis F, Julienne A, Hanauer A, Econs MJ, Oudet C.

Eur J Hum Genet. 1999 Jul;7(5):615-9.

PubMed [citation]

PMID:: 10439971

Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment.

Quinlan C, Guegan K, Offiah A, Neill RO, Hiorns MP, Ellard S, Bockenhauer D, Hoff WV, Waters AM.

Pediatr Nephrol. 2012 Apr;27(4):581-8. doi: 10.1007/s00467-011-2046-z. Epub 2011 Nov 20.

PubMed [citation]

PMID:: 22101457

See all PubMed Citations (4)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000341459.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From GeneDx, SCV000491263.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant has been previously published in association with X-linked hypophosphatemic rickets (Filisetti et al., 1999; Quinlan et al., 2012) with limited data to fully support pathogenicity. The W456C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W456C variant 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. A missense variant in a nearby residue (L450P) has also been reported in the Human Gene Mutation Database in association with hypophosphatemic rickets (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001396645.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp456 amino acid residue in PHEX. Other variant(s) that disrupt this residue have been observed in individuals with PHEX-related conditions (PMID: 29460029), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 287635). This missense change has been observed in individuals with hypophosphatemia (PMID: 10439971, 22101457, 29460029; Invitae). 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 replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 456 of the PHEX protein (p.Trp456Cys).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 14, 2024

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