NM_000444.6(PHEX):c.425G>C (p.Cys142Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 29, 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:: RCV000481349.10

Allele description [Variation Report for NM_000444.6(PHEX):c.425G>C (p.Cys142Ser)]

NM_000444.6(PHEX):c.425G>C (p.Cys142Ser)

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.425G>C (p.Cys142Ser)

HGVS:

NC_000023.11:g.22076463G>C
NG_007563.2:g.48661G>C
NM_000444.6:c.425G>CMANE SELECT
NM_001282754.2:c.425G>C
NP_000435.3:p.Cys142Ser
NP_001269683.1:p.Cys142Ser
NC_000023.10:g.22094581G>C
NM_000444.4:c.425G>C
NM_000444.5:c.425G>C

Protein change:

C142S

Links:

dbSNP: rs1064797048

NCBI 1000 Genomes Browser:

rs1064797048

Molecular consequence:

NM_000444.6:c.425G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001282754.2:c.425G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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PREDICTED: Homo sapiens raftlin, lipid raft linker 1 (RFTN1), transcript variant...
PREDICTED: Homo sapiens raftlin, lipid raft linker 1 (RFTN1), transcript variant X3, mRNA
gi|2462588355|ref|XM_054345825.1|

Nucleotide
PREDICTED: Homo sapiens raftlin, lipid raft linker 1 (RFTN1), transcript variant...
PREDICTED: Homo sapiens raftlin, lipid raft linker 1 (RFTN1), transcript variant X7, mRNA
gi|2462588361|ref|XM_054345828.1|

Nucleotide
PREDICTED: Homo sapiens raftlin, lipid raft linker 1 (RFTN1), transcript variant...
PREDICTED: Homo sapiens raftlin, lipid raft linker 1 (RFTN1), transcript variant X9, mRNA
gi|2217342817|ref|XM_047447783.1|

Nucleotide
PREDICTED: Homo sapiens raftlin, lipid raft linker 1 (RFTN1), transcript variant...
PREDICTED: Homo sapiens raftlin, lipid raft linker 1 (RFTN1), transcript variant X2, mRNA
gi|2462588353|ref|XM_054345824.1|

Nucleotide
raftlin isoform X2 [Homo sapiens]
raftlin isoform X2 [Homo sapiens]
gi|2217342813|ref|XP_047303736.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000574401	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Mar 23, 2017)	germline	clinical testing	Citation Link,
SCV001373535	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] 10439971, 25086671, 32253725, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000574401

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Mar 23, 2017)

germline

clinical testing

Citation Link,

SCV001373535

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	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

Targeted sequencing of a pediatric metabolic bone gene panel using a desktop semiconductor next-generation sequencer.

Rauch F, Lalic L, Glorieux FH, Moffatt P, Roughley P.

Calcif Tissue Int. 2014 Oct;95(4):323-31. doi: 10.1007/s00223-014-9897-9. Epub 2014 Aug 3.

PubMed [citation]

PMID:: 25086671

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000574401.3

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

Description

The C142S variant has been reported previously in a patient with X-linked hypophosphatemic rickets (Lo et al., 2006) with limited evidence for pathogenicity. C142S is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). It 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. Additionally, missense variants at the same (C142F/R) and in nearby residues (L138P) have 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. However, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001373535.5

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

Description

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys142 amino acid residue in PHEX. Other variant(s) that disrupt this residue have been observed in individuals with PHEX-related conditions (PMID: 10439971, 25086671), 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: 424579). This missense change has been observed in individual(s) with clinical features of hhypophosphatemic rickets (PMID: 32253725). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 142 of the PHEX protein (p.Cys142Ser).

#	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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