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

dbSNP: rs1555716575

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521481	SCV000620225	likely pathogenic	not provided	2024-10-21	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24706940, 35718083)
Institute of Human Genetics, University of Leipzig Medical Center	RCV001844185	SCV005368274	likely pathogenic	Spondylometaphyseal dysplasia, Sedaghatian type	2024-06-17	criteria provided, single submitter	clinical testing	Criteria applied: PVS1_STR,PM2,PM3
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001844185	SCV001870477	pathogenic	Spondylometaphyseal dysplasia, Sedaghatian type	2021-04-29	no assertion criteria provided	research
Royal Medical Services, Bahrain Defence Force Hospital	RCV001844185	SCV005061399	uncertain significance	Spondylometaphyseal dysplasia, Sedaghatian type		no assertion criteria provided	clinical testing	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.