NM_000444.6(PHEX):c.2239C>T (p.Arg747Ter) AND Familial X-linked hypophosphatemic vitamin D refractory rickets

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jan 12, 2024
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:: RCV000505449.10

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]

Observations:

Condition(s)

Name:: Familial X-linked hypophosphatemic vitamin D refractory rickets (XLHRD)
Synonyms:: HYPOPHOSPHATEMIC VITAMIN D-RESISTANT RICKETS; Hypophosphatemic Rickets, X-Linked Dominant; Hypophosphatemia, vitamin D-resistant rickets; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010619; MedGen: C0733682; Orphanet: 89936; OMIM: 307800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000599629	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Oct 28, 2013)	de novo, germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000893828	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002767959	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 28, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004231766	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004814110	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	6	not provided	not provided	6	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	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
not provided	de novo	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Genomic organization of the human PEX gene mutated in X-linked dominant hypophosphatemic rickets.

Francis F, Strom TM, Hennig S, Böddrich A, Lorenz B, Brandau O, Mohnike KL, Cagnoli M, Steffens C, Klages S, Borzym K, Pohl T, Oudet C, Econs MJ, Rowe PS, Reinhardt R, Meitinger T, Lehrach H.

Genome Res. 1997 Jun;7(6):573-85. No abstract available.

PubMed [citation]

PMID:: 9199930

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000599629.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)
2	not provided	1	not provided	not provided	clinical testing	PubMed (1)
3	not provided	1	not provided	not provided	clinical testing	PubMed (1)
4	not provided	1	not provided	not provided	clinical testing	PubMed (1)
5	not provided	1	not provided	not provided	clinical testing	PubMed (1)
6	not provided	1	not provided	not provided	clinical testing	PubMed (1)
7	not provided	1	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	1	blood	not provided		1	not provided	not provided	not provided
2	germline	yes	1	blood	not provided		1	not provided	not provided	not provided
3	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided
4	germline	yes	1	blood	not provided		1	not provided	not provided	not provided
5	germline	yes	1	blood	not provided		1	not provided	not provided	not provided
6	germline	yes	1	blood	not provided		1	not provided	not provided	not provided
7	germline	yes	1	blood	not provided		1	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893828.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767959.1

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

Description

A hemizygous nonsense variant was identified NM_000444.5(PHEX):c.2239C>T in exon 22 of 22 of the PHEX gene. This nonsense variant is predicted to create a change of arginine to a stop at amino acid position 747 of the protein, NP_000435.3(PHEX):p.(Arg747*), resulting in the loss of normal protein function through truncation. The variant is not present in the gnomAD population database. The variant has previously been reported as pathogenic and segregated with disease in multiple families with X-linked dominant hypophosphatemic rickets (ClinVar, Francis, F. et al. (1997), Holm, I. et al. (2001), Capelli, S. et al. (2015), Acar, S. et al. (2018)). Based on information available at the time of curation, 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004231766.2

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV004814110.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	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	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Nov 24, 2024

ClinVar

Relating variation to medicine