NM_002085.5(GPX4):c.502-1del AND Spondylometaphyseal dysplasia, Sedaghatian type

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Jun 17, 2024
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:: RCV001844185.5

Allele description [Variation Report for NM_002085.5(GPX4):c.502-1del]

NM_002085.5(GPX4):c.502-1del

Gene:

GPX4:glutathione peroxidase 4 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

19p13.3

Genomic location:

Preferred name:

NM_002085.5(GPX4):c.502-1del

HGVS:

NC_000019.10:g.1106399del
NG_050621.1:g.7474del
NG_139817.1:g.80del
NM_001039847.2:c.523del
NM_001039847.3:c.523del
NM_001039848.4:c.613-1del
NM_001367832.1:c.421-1del
NM_002085.5:c.502-1delMANE SELECT
NP_001034936.1:p.Val175fs
NC_000019.9:g.1106398del
NM_001039848.2:c.613-1delG
NM_002085.5:c.502-1del

Protein change:

V175fs

Links:

dbSNP: rs1555716575

NCBI 1000 Genomes Browser:

rs1555716575

Molecular consequence:

NM_001039847.3:c.523del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001039848.4:c.613-1del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001367832.1:c.421-1del - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_002085.5:c.502-1del - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Name:: Spondylometaphyseal dysplasia, Sedaghatian type
Synonyms:: METAPHYSEAL CHONDRODYSPLASIA, CONGENITAL LETHAL; SEDAGHATIAN CHONDRODYSPLASIA; Lethal metaphyseal dysplasia
Identifiers:: MONDO: MONDO:0009593; MedGen: C1855229; Orphanet: 93317; OMIM: 250220

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001870477	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	no assertion criteria provided	Pathogenic (Apr 29, 2021)	germline	research
SCV005061399	Royal Medical Services, Bahrain Defence Force Hospital	no assertion criteria provided	Uncertain significance	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005368274	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 17, 2024)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001870477

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

no assertion criteria provided

Pathogenic
(Apr 29, 2021)

germline

research

SCV005061399

Royal Medical Services, Bahrain Defence Force Hospital

no assertion criteria provided

Uncertain significance

inherited

clinical testing

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

SCV005368274

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 17, 2024)

inherited

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	research
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
Arab	inherited	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the enzyme glutathione peroxidase 4 cause Sedaghatian-type spondylometaphyseal dysplasia.

Smith AC, Mears AJ, Bunker R, Ahmed A, MacKenzie M, Schwartzentruber JA, Beaulieu CL, Ferretti E; FORGE Canada Consortium, Majewski J, Bulman DE, Celik FC, Boycott KM, Graham GE.

J Med Genet. 2014 Jul;51(7):470-4. doi: 10.1136/jmedgenet-2013-102218. Epub 2014 Apr 4.

PubMed [citation]

PMID:: 24706940

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

Details of each submission

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV001870477.1

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

#	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 Royal Medical Services, Bahrain Defence Force Hospital, SCV005061399.1

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

Description

The GPX4 variant c.523del p.(Val175Phefs*?) creates a shift in the reading frame starting at codon 175 with unknown location of the terminating stop codon. According to HGMD Professional 2020.3, loss of function is not known disease mechanism for this gene. To date, only one loss of function variant has been described. In gnomAD, the GPX4 gene seems to be tolerant for loss of function (pLI = 0). This variant has not yet been described in the literature in individuals with GPX4-related disorder. ClinVar lists this variant as uncertain (clinical testing, Variation ID: 451510). Thus, it is classified as variant of uncertain significance (class 3) according to the recommendations of CENTOGENE and ACMG.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV005368274.1

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

Description

Criteria applied: PVS1_STR,PM2,PM3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 18, 2024

ClinVar

Relating variation to medicine