VCV000866381.41 - ClinVar

NM_001034853.2(RPGR):c.3092del (p.Glu1031fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001034853.2(RPGR):c.3092del (p.Glu1031fs)

Variation ID: 866381 Accession: VCV000866381.41

Type and length

Deletion, 1 bp

Location

Cytogenetic: Xp11.4 X: 38285907 (GRCh38) [ NCBI UCSC ] X: 38145160 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 18, 2020	Nov 24, 2024	Oct 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001034853.2:c.3092del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001030025.1:p.Glu1031fs	frameshift
NM_000328.3:c.1905+1187del		intron variant
NM_001034853.1:c.3092delA
NM_001367245.1:c.1902+1187del		intron variant
NM_001367246.1:c.1719+1187del		intron variant
NM_001367247.1:c.1572+5052del		intron variant
NM_001367248.1:c.1602+5052del		intron variant
NM_001367249.1:c.1569+5052del		intron variant
NM_001367250.1:c.1569+5052del		intron variant
NM_001367251.1:c.1386+5052del		intron variant
NC_000023.11:g.38285907del
NC_000023.10:g.38145160del
NG_009553.1:g.46629del

... more HGVS ... less HGVS

Protein change

E1031fs

Other names

Canonical SPDI

NC_000023.11:38285906:T:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

dbSNP: rs1186795749 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RPGR		-	-	GRCh38 GRCh37	1512	1685

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Jun 29, 2019	RCV001074314.4
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 1, 2024	RCV001090908.29
Retinitis pigmentosa 3	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Oct 8, 2024	RCV001251566.6
Retinitis pigmentosa	Pathogenic (1)	criteria provided, single submitter	Apr 1, 2021	RCV001724237.5
X-linked cone-rod dystrophy 1	Pathogenic (1)	criteria provided, single submitter	Feb 15, 2022	RCV002290587.4
Primary ciliary dyskinesia	Pathogenic (1)	criteria provided, single submitter	Oct 5, 2023	RCV002557909.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jun 29, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239887.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Apr 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinitis pigmentosa 3 Affected status: yes Allele origin: germline	Ocular Genomics Institute, Massachusetts Eye and Ear Accession: SCV001573326.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (1) PubMed: 31645972 Comment: The RPGR c.3092del variant was identified in an individual with retinitis pigmentosa with a presumed X-linked inheritance pattern. Through a review of available evidence we … (more) The RPGR c.3092del 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, PP3, PM2, PP1-M. Based on this evidence we have classified this variant as Pathogenic. (less)
Pathogenic (Apr 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Retinitis pigmentosa (X-linked inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001950366.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Publications: PubMed (2) PubMed: 34906470‚ 31645972 Comment: The p.Glu1031GlyfsTer58 variant in RPGR was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more) The p.Glu1031GlyfsTer58 variant in RPGR was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PP3, PM2, PP1-M. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 3 Affected status: yes Allele origin: germline	3billion Accession: SCV002058896.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:31645972 PMID:31645972 Comment: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported … (more) Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic (ClinVar ID: VCV000866381, PMID: 31645972). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Visual impairment (present) , Abnormal retinal morphology (present)
Pathogenic (Feb 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	X-linked cone-rod dystrophy 1 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580631.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PM2_SUP, PP1	Number of individuals with the variant: 1 Sex: male
Pathogenic (Nov 13, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV002759696.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022
Pathogenic (Sep 11, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003840811.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Comment: Frameshift variant predicted to result in protein truncation, as the last 122 amino acids are replaced with 57 different amino acids, and other loss-of-function variants … (more) Frameshift variant predicted to result in protein truncation, as the last 122 amino acids are replaced with 57 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Also known as ORF15+1339delA; This variant is associated with the following publications: (PMID: 33355362, 30567410, 24077912, 31804667, 31645972, 32795431, 12657579, 18332319, 18552978, 27798110) (less)
Pathogenic (Oct 05, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Primary ciliary dyskinesia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003445110.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 12657579‚ 18332319‚ 31804667‚ 22264887 Comment: This sequence change creates a premature translational stop signal (p.Glu1031Glyfs58) in the RPGR (ORF15) gene. While this is not anticipated to result in nonsense mediated … (more) This sequence change creates a premature translational stop signal (p.Glu1031Glyfs58) in the RPGR (ORF15) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 122 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 retinitis pigmentosa (PMID: 12657579, 18332319, 31804667). This variant is also known as ORF15+1339delA. ClinVar contains an entry for this variant (Variation ID: 866381). 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. (less)
Pathogenic (Apr 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246679.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: RPGR: PVS1:Strong, PM1, PM2, PS4:Moderate Number of individuals with the variant: 4
Pathogenic (Oct 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 3 Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398445.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (9) PubMed: 10932196‚ 14691151‚ 17195164‚ 23372056‚ 23681342‚ 27620828‚ 27995965‚ 30193314‚ 31953110 Comment: Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss-of-function is a known mechanism of disease … (more) Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss-of-function is a known mechanism of disease for this gene. Gain-of-function has also been suggested as a mechanism for truncating variants in ORF15 (PMID: 14691151; PMID: 27995965). (N) 0109 - This gene is known to be associated with X-linked recessive disease. This gene is predominantly associated with X-linked recessive disease, however dominant inheritance patterns have also been reported for some variants (OMIM, PMID: 23372056). X-inactivation was associated with variable severity in females (PMID: 31953110). (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 15 of 15). Exon 15 is also known as ORF15 in the NM_001034853.1 transcript (PMID: 30193314). (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Other variants located dowsntream and predicted to cause a truncated protein have been reported as pathogenic in individuals with retinal dystrophy (ClinVar; PMID: 23681342; 23372056, 27620828). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories in ClinVar and reported in individuals with retinitis pigmentosa (PMID: 17195164; 10932196). (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Retinitis pigmentosa 3 Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001427346.1 First in ClinVar: Aug 13, 2020 Last updated: Aug 13, 2020
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Comment:

The RPGR c.3092del 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, PP3, PM2, PP1-M. Based on this evidence we have classified this variant as Pathogenic.

Comment:

The p.Glu1031GlyfsTer58 variant in RPGR was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PP3, PM2, PP1-M. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.

Comment:

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic (ClinVar ID: VCV000866381, PMID: 31645972). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Frameshift variant predicted to result in protein truncation, as the last 122 amino acids are replaced with 57 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Also known as ORF15+1339delA; This variant is associated with the following publications: (PMID: 33355362, 30567410, 24077912, 31804667, 31645972, 32795431, 12657579, 18332319, 18552978, 27798110)

Comment:

This sequence change creates a premature translational stop signal (p.Glu1031Glyfs*58) in the RPGR (ORF15) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 122 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 retinitis pigmentosa (PMID: 12657579, 18332319, 31804667). This variant is also known as ORF15+1339delA. ClinVar contains an entry for this variant (Variation ID: 866381). 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.

Comment:

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss-of-function is a known mechanism of disease for this gene. Gain-of-function has also been suggested as a mechanism for truncating variants in ORF15 (PMID: 14691151; PMID: 27995965). (N) 0109 - This gene is known to be associated with X-linked recessive disease. This gene is predominantly associated with X-linked recessive disease, however dominant inheritance patterns have also been reported for some variants (OMIM, PMID: 23372056). X-inactivation was associated with variable severity in females (PMID: 31953110). (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 15 of 15). Exon 15 is also known as ORF15 in the NM_001034853.1 transcript (PMID: 30193314). (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Other variants located dowsntream and predicted to cause a truncated protein have been reported as pathogenic in individuals with retinal dystrophy (ClinVar; PMID: 23681342; 23372056, 27620828). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories in ClinVar and reported in individuals with retinitis pigmentosa (PMID: 17195164; 10932196). (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK).	Zampaglione E	Genetics in medicine : official journal of the American College of Medical Genetics	2022	PMID: 34906470
X-Chromosome Inactivation Is a Biomarker of Clinical Severity in Female Carriers of RPGR-Associated X-Linked Retinitis Pigmentosa.	Fahim AT	Ophthalmology. Retina	2020	PMID: 31953110
Reanalysis of Association of Pro50Leu Substitution in Guanylate Cyclase Activating Protein-1 With Dominant Retinal Dystrophy.	Mahroo OA	JAMA ophthalmology	2020	PMID: 31804667
Clinical and genetic characteristics of 14 patients from 13 Japanese families with RPGR-associated retinal disorder: report of eight novel variants.	Mawatari G	Human genome variation	2019	PMID: 31645972
Development of High-Throughput Clinical Testing of RPGR ORF15 Using a Large Inherited Retinal Dystrophy Cohort.	Chiang JPW	Investigative ophthalmology & visual science	2018	PMID: 30193314
Identification of novel X-linked gain-of-function RPGR-ORF15 mutation in Italian family with retinitis pigmentosa and pathologic myopia.	Parmeggiani F	Scientific reports	2016	PMID: 27995965
Improved Diagnosis of Inherited Retinal Dystrophies by High-Fidelity PCR of ORF15 followed by Next-Generation Sequencing.	Li J	The Journal of molecular diagnostics : JMD	2016	PMID: 27620828
Phenotypic conservation in patients with X-linked retinitis pigmentosa caused by RPGR mutations.	Zahid S	JAMA ophthalmology	2013	PMID: 23681342
Mutations in the X-linked retinitis pigmentosa genes RPGR and RP2 found in 8.5% of families with a provisional diagnosis of autosomal dominant retinitis pigmentosa.	Churchill JD	Investigative ophthalmology & visual science	2013	PMID: 23372056
Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy.	Thiadens AA	Ophthalmology	2012	PMID: 22264887
Discordant phenotypes in fraternal twins having an identical mutation in exon ORF15 of the RPGR gene.	Walia S	Archives of ophthalmology (Chicago, Ill. : 1960)	2008	PMID: 18332319
RPGR mutation analysis and disease: an update.	Shu X	Human mutation	2007	PMID: 17195164
Dominant, gain-of-function mutant produced by truncation of RPGR.	Hong DH	Investigative ophthalmology & visual science	2004	PMID: 14691151
X-linked retinitis pigmentosa: RPGR mutations in most families with definite X linkage and clustering of mutations in a short sequence stretch of exon ORF15.	Bader I	Investigative ophthalmology & visual science	2003	PMID: 12657579
Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa.	Vervoort R	Nature genetics	2000	PMID: 10932196
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Text-mined citations for rs1186795749 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001034853.2(RPGR):c.3092del (p.Glu1031fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1186795749 ...