X-38285901-TCC-T

Variant names:

• chrX-38285901-TCC-T
• rs606231180
• NM_001034853.2:c.3096_3097delGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_001034853.2(RPGR):​c.3096_3097delGG​(p.Glu1033ArgfsTer45) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: RPGR NM_001034853.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: -0.117

Genes affected

RPGR (HGNC:10295): (retinitis pigmentosa GTPase regulator) This gene encodes a protein with a series of six RCC1-like domains (RLDs), characteristic of the highly conserved guanine nucleotide exchange factors. The encoded protein is found in the Golgi body and interacts with RPGRIP1. This protein localizes to the outer segment of rod photoreceptors and is essential for their viability. Mutations in this gene have been associated with X-linked retinitis pigmentosa (XLRP). Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but the full-length natures of only some have been determined. [provided by RefSeq, Dec 2008]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.105 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PP5: Variant X-38285901-TCC-T is Pathogenic according to our data. Variant chrX-38285901-TCC-T is described in ClinVar as [Pathogenic]. Clinvar id is 9910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38285901-TCC-T is described in Lovd as [Pathogenic]. Variant chrX-38285901-TCC-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.3096_3097delGG	p.Glu1033ArgfsTer45	frameshift_variant	Exon 15 of 15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.3096_3097delGG	p.Glu1033ArgfsTer45	frameshift_variant	Exon 15 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-380216_172-380215delCC		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000279 AC: 3 AN: 1074426 Hom.: 0 AF XY: 0.00000289 AC XY: 1 AN XY: 346148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 17

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked cone-rod dystrophy 1 Pathogenic:3

Oct 09, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2016

Edmonton Ocular Genetics, Alberta Health Services

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Apr 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Retinitis pigmentosa 3 Pathogenic:2

-

Blueprint Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

RPGR-related disorder Pathogenic:1

Mar 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Cone dystrophy 1, X-linked Pathogenic:1

Apr 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Primary ciliary dyskinesia Pathogenic:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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; internal data). 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. -

Retinal dystrophy Pathogenic:1

Apr 03, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone dystrophy Pathogenic:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

RPGR-related retinopathy Pathogenic:1

May 02, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs606231180; hg19: chrX-38145154;