VCV000812418.13 - ClinVar

NM_001034853.2(RPGR):c.1243_1244del (p.Arg415fs)

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.

(5)

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.1243_1244del (p.Arg415fs)

Variation ID: 812418 Accession: VCV000812418.13

Type and length

Microsatellite, 2 bp

Location

Cytogenetic: Xp11.4 X: 38298957-38298958 (GRCh38) [ NCBI UCSC ] X: 38158210-38158211 (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	Feb 16, 2020	May 1, 2024	Oct 20, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001034853.2:c.1243_1244del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001030025.1:p.Arg415fs	frameshift
NM_000328.3:c.1243_1244del	NP_000319.1:p.Arg415fs	frameshift
NM_001034853.1:c.1243_1244del
NM_001367245.1:c.1240_1241del	NP_001354174.1:p.Arg414fs	frameshift
NM_001367246.1:c.1060-1512AG[3]		intron variant
NM_001367247.1:c.1243_1244del	NP_001354176.1:p.Arg415fs	frameshift
NM_001367248.1:c.1273_1274del	NP_001354177.1:p.Arg425fs	frameshift
NM_001367249.1:c.1240_1241del	NP_001354178.1:p.Arg414fs	frameshift
NM_001367250.1:c.1240_1241del	NP_001354179.1:p.Arg414fs	frameshift
NM_001367251.1:c.1060-1512AG[3]		intron variant
NR_159803.1:n.1439AG[3]		non-coding transcript variant
NR_159804.1:n.1288AG[3]		non-coding transcript variant
NR_159805.1:n.1379AG[3]		non-coding transcript variant
NR_159806.1:n.1379AG[3]		non-coding transcript variant
NR_159807.1:n.1379AG[3]		non-coding transcript variant
NR_159808.1:n.1491AG[3]		non-coding transcript variant
NC_000023.11:g.38298957CT[3]
NC_000023.10:g.38158210CT[3]
NG_009553.1:g.33572AG[3]

... more HGVS ... less HGVS

Protein change

R414fs, R415fs, R425fs

Other names

Canonical SPDI

NC_000023.11:38298956:CTCTCTCT:CTCTCT

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.

Links

dbSNP: rs281865302 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	Nov 30, 2017	RCV001073760.3
Primary ciliary dyskinesia	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 20, 2022	RCV001387576.10
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 27, 2016	RCV002464355.6
Retinitis pigmentosa	Pathogenic (1)	no assertion criteria provided	Jun 23, 2019	RCV001003201.2

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 (Nov 30, 2017)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239320.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Oct 20, 2022)	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: SCV001588244.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 14516808‚ 28322733‚ 30924848‚ 31953110‚ 16055928‚ 16969763 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This premature translational stop signal has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 14516808, 28322733, 30924848, 31953110). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg415Glyfs*37) in the RPGR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPGR are known to be pathogenic (PMID: 16055928, 16969763). (less)
Pathogenic (Sep 27, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV002759623.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022
Pathogenic (Mar 22, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Primary ciliary dyskinesia Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002673083.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 14516808‚ 23950152‚ 28322733‚ 28912962 Comment: The c.1243_1244delAG pathogenic mutation, located in coding exon 10 of the RPGR gene, results from a deletion of two nucleotides at nucleotide positions 1243 to … (more) The c.1243_1244delAG pathogenic mutation, located in coding exon 10 of the RPGR gene, results from a deletion of two nucleotides at nucleotide positions 1243 to 1244, causing a translational frameshift with a predicted alternate stop codon (p.R415Gfs*37). This mutation was identified in multiple families with individuals diagnosed with retinitis pigmentosa (Sullivan LS et al. Invest. Ophthalmol. Vis. Sci., 2013 Sep;54:6255-61; Tee JJL et al. Am. J. Ophthalmol., 2017 Jun;178:18-26; Costa KA et al. Int J Retina Vitreous, 2017 Sep;3:33). In one family, this mutation was identified in 15 affected individuals with a varying visual phenotypes; some individuals also had hearing loss (Koenekoop RK et al. Am. J. Ophthalmol., 2003 Oct;136:678-87). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001161279.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This premature translational stop signal has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 14516808, 28322733, 30924848, 31953110). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg415Glyfs*37) in the RPGR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPGR are known to be pathogenic (PMID: 16055928, 16969763).

Comment:

The c.1243_1244delAG pathogenic mutation, located in coding exon 10 of the RPGR gene, results from a deletion of two nucleotides at nucleotide positions 1243 to 1244, causing a translational frameshift with a predicted alternate stop codon (p.R415Gfs*37). This mutation was identified in multiple families with individuals diagnosed with retinitis pigmentosa (Sullivan LS et al. Invest. Ophthalmol. Vis. Sci., 2013 Sep;54:6255-61; Tee JJL et al. Am. J. Ophthalmol., 2017 Jun;178:18-26; Costa KA et al. Int J Retina Vitreous, 2017 Sep;3:33). In one family, this mutation was identified in 15 affected individuals with a varying visual phenotypes; some individuals also had hearing loss (Koenekoop RK et al. Am. J. Ophthalmol., 2003 Oct;136:678-87). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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
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
Cone Spacing Correlates With Retinal Thickness and Microperimetry in Patients With Inherited Retinal Degenerations.	Foote KG	Investigative ophthalmology & visual science	2019	PMID: 30924848
Gene panel sequencing in Brazilian patients with retinitis pigmentosa.	Costa KA	International journal of retina and vitreous	2017	PMID: 28912962
Quantitative Analysis of Retinal Structure Using Spectral-Domain Optical Coherence Tomography in RPGR-Associated Retinopathy.	Tee JJL	American journal of ophthalmology	2017	PMID: 28322733
Prevalence of mutations in eyeGENE probands with a diagnosis of autosomal dominant retinitis pigmentosa.	Sullivan LS	Investigative ophthalmology & visual science	2013	PMID: 23950152
Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype-phenotype correlations and impact on genetic counseling.	Pelletier V	Human mutation	2007	PMID: 16969763
RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa.	Moore A	Journal of medical genetics	2006	PMID: 16055928
Novel RPGR mutations with distinct retinitis pigmentosa phenotypes in French-Canadian families.	Koenekoop RK	American journal of ophthalmology	2003	PMID: 14516808

Text-mined citations for rs281865302 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001034853.2(RPGR):c.1243_1244del (p.Arg415fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs281865302 ...