NM_000444.6(PHEX):c.2239C>T (p.Arg747Ter) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: May 25, 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:: RCV000351204.11

Allele description [Variation Report for NM_000444.6(PHEX):c.2239C>T (p.Arg747Ter)]

NM_000444.6(PHEX):c.2239C>T (p.Arg747Ter)

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.2239C>T (p.Arg747Ter)

HGVS:

NC_000023.11:g.22247942C>T
NG_007563.2:g.220139C>T
NM_000444.6:c.2239C>TMANE SELECT
NM_001282754.2:c.*74C>T
NP_000435.3:p.Arg747Ter
NC_000023.10:g.22266059C>T
NM_000444.4:c.2239C>T
NM_000444.5:c.2239C>T

Protein change:

R747*

Links:

dbSNP: rs886041227

NCBI 1000 Genomes Browser:

rs886041227

Molecular consequence:

NM_001282754.2:c.*74C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000444.6:c.2239C>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
SCV000329465	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 14, 2022)	germline	clinical testing	Citation Link,
SCV000843046	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Dec 7, 2017)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9768674, 10439971, 14564066, 14564077, 16055933, 9199930, 21902834, 19219621, 26467025
SCV001374163	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 25, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9199930, 9768674, 28492532
SCV005197124	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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

X-linked hypophosphatemia in Polish patients. 2. Analysis of clinical features and genotype-phenotype correlation.

Popowska E, Pronicka E, Sułek A, Jurkiewicz D, Rowińska E, Sykut-Cegielska J, Rump Z, Arasimowicz E, Krajewska-Walasek M.

J Appl Genet. 2001;42(1):73-88.

PubMed [citation]

PMID:: 14564066

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000329465.8

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

Description

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 3 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25894638, 24926462, 29505567, 9768674, 9199930, 26051471, 10439971, 11502829, 16055933, 21902834, 30607568, 30682568, 32253725, 32329911, 33666701, 34141703)

#	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 Athena Diagnostics, SCV000843046.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	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

From Invitae, SCV001374163.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 279873). This premature translational stop signal has been observed in individuals with X-linked dominant hypophosphatemic rickets (PMID: 9199930, 9768674). 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 creates a premature translational stop signal (p.Arg747*) in the PHEX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acid(s) of the PHEX protein.

#	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

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005197124.1

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

#	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

Last Updated: Sep 1, 2024

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