NM_000444.6(PHEX):c.1960T>A (p.Phe654Ile) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 21, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001340539.8

Allele description [Variation Report for NM_000444.6(PHEX):c.1960T>A (p.Phe654Ile)]

NM_000444.6(PHEX):c.1960T>A (p.Phe654Ile)

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.1960T>A (p.Phe654Ile)

HGVS:

NC_000023.11:g.22226503T>A
NG_007563.2:g.198700T>A
NM_000444.4:c.1960T>A
NM_000444.6:c.1960T>AMANE SELECT
NM_001282754.2:c.1960T>A
NP_000435.3:p.Phe654Ile
NP_001269683.1:p.Phe654Ile
NC_000023.10:g.22244620T>A

Protein change:

F654I

Links:

dbSNP: rs1935508894

NCBI 1000 Genomes Browser:

rs1935508894

Molecular consequence:

NM_000444.6:c.1960T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282754.2:c.1960T>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001534355	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 21, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004229839	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Uncertain significance (Aug 14, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34806794, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001534355

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 21, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004229839

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Uncertain significance
(Aug 14, 2023)

unknown

clinical testing

PubMed (2)
[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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Novel PHEX gene locus-specific database: Comprehensive characterization of vast number of variants associated with X-linked hypophosphatemia (XLH).

Sarafrazi S, Daugherty SC, Miller N, Boada P, Carpenter TO, Chunn L, Dill K, Econs MJ, Eisenbeis S, Imel EA, Johnson B, Kiel MJ, Krolczyk S, Ramesan P, Truty R, Sabbagh Y.

Hum Mutat. 2022 Feb;43(2):143-157. doi: 10.1002/humu.24296. Epub 2021 Dec 5.

PubMed [citation]

PMID:: 34806794
PMCID:: PMC9299612

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001534355.4

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

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 654 of the PHEX protein (p.Phe654Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hypophosphatemic rickets and/or PHEX-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 1037395). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PHEX protein function with a positive predictive value of 80%. 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.

#	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 Athena Diagnostics, SCV004229839.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Available data are insufficient to determine the clinical significance of the variant at this time. This variant has been identified in at least one individual with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.

#	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

Last Updated: May 7, 2024

ClinVar

Relating variation to medicine