NM_000444.6(PHEX):c.1543C>T (p.Gln515Ter) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000333172.7

Allele description [Variation Report for NM_000444.6(PHEX):c.1543C>T (p.Gln515Ter)]

NM_000444.6(PHEX):c.1543C>T (p.Gln515Ter)

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.1543C>T (p.Gln515Ter)

HGVS:

NC_000023.11:g.22178333C>T
NG_007563.2:g.150530C>T
NM_000444.6:c.1543C>TMANE SELECT
NM_001282754.2:c.1543C>T
NP_000435.3:p.Gln515Ter
NP_001269683.1:p.Gln515Ter
NC_000023.10:g.22196450C>T
NM_000444.4:c.1543C>T
NM_000444.5:c.1543C>T

Protein change:

Q515*

Links:

dbSNP: rs886041361

NCBI 1000 Genomes Browser:

rs886041361

Molecular consequence:

NM_000444.6:c.1543C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001282754.2:c.1543C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000329876	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Apr 19, 2017)	germline	clinical testing	Citation Link,
SCV001402417	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 17, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9097956, 9106524, 19219621, 21902834, 30682568, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000329876

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Apr 19, 2017)

germline

clinical testing

Citation Link,

SCV001402417

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 17, 2023)

germline

clinical testing

PubMed (6)
[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

Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP).

Rowe PS, Oudet CL, Francis F, Sinding C, Pannetier S, Econs MJ, Strom TM, Meitinger T, Garabedian M, David A, Macher MA, Questiaux E, Popowska E, Pronicka E, Read AP, Mokrzycki A, Glorieux FH, Drezner MK, Hanauer A, Lehrach H, Goulding JN, O'Riordan JL.

Hum Mol Genet. 1997 Apr;6(4):539-49.

PubMed [citation]

PMID:: 9097956

Mutational analysis of the PEX gene in patients with X-linked hypophosphatemic rickets.

Holm IA, Huang X, Kunkel LM.

Am J Hum Genet. 1997 Apr;60(4):790-7.

PubMed [citation]

PMID:: 9106524
PMCID:: PMC1712471

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000329876.5

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

Description

The Q515X nonsense variant in the PHEX gene has been reported as a de novo finding in patients with X-linked hypophosphatemic rickets (Morey et al., 2011; Durmaz et al., 2013; Zhang et al., 2015). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In addition, the Q515X variant was not observed in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. Therefore, we interpret the Q515X variant to be pathogenic.

#	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, SCV001402417.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change creates a premature translational stop signal (p.Gln515*) in the PHEX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PHEX are known to be pathogenic (PMID: 9097956, 9106524, 19219621). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hypophosphatemic rickets (PMID: 21902834, 30682568). ClinVar contains an entry for this variant (Variation ID: 280074). For these reasons, this variant has been classified as Pathogenic.

#	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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