NM_000444.6(PHEX):c.2198G>C (p.Cys733Ser) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 29, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001307376.7

Allele description [Variation Report for NM_000444.6(PHEX):c.2198G>C (p.Cys733Ser)]

NM_000444.6(PHEX):c.2198G>C (p.Cys733Ser)

Genes:

PTCHD1-AS:PTCHD1 antisense RNA (head to head) [Gene - HGNC]
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.2198G>C (p.Cys733Ser)

HGVS:

NC_000023.11:g.22247901G>C
NG_007563.2:g.220098G>C
NM_000444.6:c.2198G>CMANE SELECT
NM_001282754.2:c.*33G>C
NP_000435.3:p.Cys733Ser
NC_000023.10:g.22266018G>C

Protein change:

C733S

Links:

dbSNP: rs1057517981

NCBI 1000 Genomes Browser:

rs1057517981

Molecular consequence:

NM_001282754.2:c.*33G>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000444.6:c.2198G>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001496786	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22527485, 25839938, 10439971, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001496786

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 29, 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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis.

Sabrautzki S, Rubio-Aliaga I, Hans W, Fuchs H, Rathkolb B, Calzada-Wack J, Cohrs CM, Klaften M, Seedorf H, Eck S, Benet-Pagès A, Favor J, Esposito I, Strom TM, Wolf E, Lorenz-Depiereux B, Hrabě de Angelis M.

Mamm Genome. 2012 Aug;23(7-8):416-30. doi: 10.1007/s00335-012-9397-z. Epub 2012 Apr 21. Erratum in: Mamm Genome. 2014 Dec;25(11-12):648.

PubMed [citation]

PMID:: 22527485
PMCID:: PMC3401305

Novel de novo nonsense mutation of the PHEX gene (p.Lys50Ter) in a Chinese patient with hypophosphatemic rickets.

Huang Y, Mei L, Pan Q, Tan H, Quan Y, Gui B, Chang J, Ma R, Peng Y, Yang P, Liang D, Wu L.

Gene. 2015 Jul 1;565(1):150-4. doi: 10.1016/j.gene.2015.03.066. Epub 2015 Mar 31.

PubMed [citation]

PMID:: 25839938

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001496786.4

#	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.Cys733 amino acid residue in PHEX. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22527485, 25839938). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 438487). This missense change has been observed in individuals with X-linked hypophosphatemia (XLH) (PMID: 10439971; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 733 of the PHEX protein (p.Cys733Ser).

#	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: Sep 29, 2024

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