NM_000444.6(PHEX):c.733-2A>T AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 7, 2021
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:: RCV000402064.5

Allele description [Variation Report for NM_000444.6(PHEX):c.733-2A>T]

NM_000444.6(PHEX):c.733-2A>T

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.733-2A>T

HGVS:

NC_000023.11:g.22093981A>T
NG_007563.2:g.66179A>T
NG_007563.3:g.66658A>T
NM_000444.6:c.733-2A>TMANE SELECT
NM_001282754.2:c.733-2A>T
NC_000023.10:g.22112099A>T
NM_000444.4:c.733-2A>T

Links:

dbSNP: rs886041496

NCBI 1000 Genomes Browser:

rs886041496

Molecular consequence:

NM_000444.6:c.733-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001282754.2:c.733-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000330161	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jan 5, 2016)	germline	clinical testing	Citation Link,
SCV002247474	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 7, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7550339, 16199547, 9097956, 9106524, 19219621, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000330161

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Jan 5, 2016)

germline

clinical testing

Citation Link,

SCV002247474

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 7, 2021)

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

A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium.

[No authors listed]

Nat Genet. 1995 Oct;11(2):130-6.

PubMed [citation]

PMID:: 7550339

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000330161.6

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

Description

The c.733-2 A>T splice site variant in the PHEX gene destroys the canonical splice acceptor site in intron 6. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. In addition, the c733-2 A>T splice variant was not observed in 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. Although this pathogenic variant has not been previously reported to our knowledge, we interpret it 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, SCV002247474.3

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

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 280260). Disruption of this splice site has been observed in individuals with clinical features of hypophosphatemic rickets (PMID: 7550339, 9097956; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 6 of the PHEX gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PHEX are known to be pathogenic (PMID: 9097956, 9106524, 19219621).

#	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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