ClinVar Miner

Submissions for variant NM_001034853.2(RPGR):c.3096_3097del (p.Glu1033fs)

dbSNP: rs606231180
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV001074702 SCV001240295 pathogenic Retinal dystrophy 2019-04-03 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001251568 SCV001573285 pathogenic Retinitis pigmentosa 3 2021-04-08 criteria provided, single submitter research The RPGR c.3096_3097del variant was identified in an individual with retinitis pigmentosa with a presumed X-linked inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PS1, PM2. Based on this evidence we have classified this variant as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003389748 SCV002759492 pathogenic RPGR-related disorder 2023-03-08 criteria provided, single submitter clinical testing The RPGR c.3096_3097delGG variant is predicted to result in a frameshift and premature protein termination (p.Glu1033Argfs*45). This variant can also be designated as g.ORF15+1343_1344del. This variant has been reported in several individuals with retinitis pigmentosa (Yang et al. 2002. PubMed ID: 11875055; Demirci et al. 2002. PubMed ID: 11857109; Table S1 in Maeda et al. 2018. PubMed ID: 29785639; Tuupanen et al. 2022. PubMed ID: 34985506). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in RPGR are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/9910). Given the evidence, we interpret c.3096_3097del (p.Glu1033Argfs*45) as pathogenic.
Invitae RCV002512962 SCV003496552 pathogenic Primary ciliary dyskinesia 2023-10-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1033Argfs*45) in the RPGR (ORF15) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 120 amino acid(s) of the RPGR (ORF15) protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cone dystrophy (PMID: 11875055, 29785639). This variant is also known as ORF15+1343_1344delGG. ClinVar contains an entry for this variant (Variation ID: 9910). This variant disrupts a region of the RPGR (ORF15) protein in which other variant(s) (p.Leu1130Lysfs*13) have been determined to be pathogenic (PMID: 22264887; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV003225923 SCV003922286 pathogenic RPGR-related retinopathy 2023-05-02 criteria provided, single submitter curation The homozygous p.Glu1033ArgfsTer45 variant in RPGR was identified by our study in one (female) individual with retinitis pigmentosa. The p.Glu1033ArgfsTer45 variant in RPGR has been previously reported in 9 unrelated individuals with RPGR-related retinopathy (PMID: 14564670, PMID: 34985506, PMID: 11857109, PMID: 29785639, PMID: 11875055, ClinVar SCV000606851.1) and segregated with disease in 22 affected relatives from three families (PMID: 11857109, PMID: 11875055). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 9910) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1033 and leads to a premature termination codon 45 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the RPGR gene is an established disease mechanism in X-linked retinitis pigmentosa 3. In summary, this variant meets criteria to be classified as pathogenic for X-linked retinitis pigmentosa 3. ACMG/AMP Criteria applied: PVS1_Moderate, PS4, PM2_Supporting, PP1_Strong (Richards 2015).
Baylor Genetics RCV000010588 SCV004209309 pathogenic X-linked cone-rod dystrophy 1 2023-10-09 criteria provided, single submitter clinical testing
OMIM RCV000010588 SCV000030814 pathogenic X-linked cone-rod dystrophy 1 2002-04-01 no assertion criteria provided literature only
Edmonton Ocular Genetics, Alberta Health Services RCV000010588 SCV000606851 pathogenic X-linked cone-rod dystrophy 1 2016-03-24 no assertion criteria provided provider interpretation Whereas this particular mutation has been associated with cone-rod dystrophy (2 families), the same variant is present in our family with X-linked RP. This then represents a first report of a patient with XLRP carrying this variant.
Sharon lab, Hadassah-Hebrew University Medical Center RCV001003190 SCV001161267 pathogenic Cone dystrophy 2019-06-23 no assertion criteria provided research
Blueprint Genetics RCV001251568 SCV001427348 pathogenic Retinitis pigmentosa 3 no assertion criteria provided clinical testing
OMIM RCV003151713 SCV003840977 pathogenic Cone dystrophy 1, X-linked 2002-04-01 no assertion criteria provided literature only

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