NM_000444.6(PHEX):c.2248T>C (p.Ter750Gln) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 20, 2020
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:: RCV001378268.6

Allele description [Variation Report for NM_000444.6(PHEX):c.2248T>C (p.Ter750Gln)]

NM_000444.6(PHEX):c.2248T>C (p.Ter750Gln)

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.2248T>C (p.Ter750Gln)

HGVS:

NC_000023.11:g.22247951T>C
NG_007563.2:g.220148T>C
NM_000444.6:c.2248T>CMANE SELECT
NM_001282754.2:c.*83T>C
NP_000435.3:p.Ter750Gln
NC_000023.10:g.22266068T>C

Links:

dbSNP: rs2147217463

NCBI 1000 Genomes Browser:

rs2147217463

Molecular consequence:

NM_001282754.2:c.*83T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000444.6:c.2248T>C - stop lost - [Sequence Ontology: SO:0001578]

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
SCV001575804	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 20, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21050253, 26051471, 30682568, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001575804

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 20, 2020)

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

Mutational analysis of PHEX, FGF23 and DMP1 in a cohort of patients with hypophosphatemic rickets.

Ruppe MD, Brosnan PG, Au KS, Tran PX, Dominguez BW, Northrup H.

Clin Endocrinol (Oxf). 2011 Mar;74(3):312-8. doi: 10.1111/j.1365-2265.2010.03919.x.

PubMed [citation]

PMID:: 21050253
PMCID:: PMC3035757

Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets.

Capelli S, Donghi V, Maruca K, Vezzoli G, Corbetta S, Brandi ML, Mora S, Weber G.

Bone. 2015 Oct;79:143-9. doi: 10.1016/j.bone.2015.05.040. Epub 2015 Jun 5.

PubMed [citation]

PMID:: 26051471

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001575804.4

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

Description

This sequence change disrupts the translational stop signal of the PHEX mRNA. It is expected to extend the length of the PHEX protein by 9 additional amino acid residues. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant results in an extension of the PHEX protein. Other variants that result in similarly extended protein products (p.*750Leuext*9, p.*750Tyrext*9) have been observed in individuals with PHEX-related conditions (PMID: 21050253, 26051471, Invitae). This suggests that these extensions may be clinically significant. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individuals with hypophosphatemia (PMID: 30682568, Invitae). This variant is not present in population databases (ExAC no frequency).

#	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: Feb 28, 2024

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