X-38286674-CCT-C

Position:

• chrX-38286674-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001034853.2(RPGR):​c.2323_2324del​(p.Arg775GlufsTer59) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000952 in 1,050,521 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 9.5e-7 (0 hom. 0 hem.)
• Consequence: RPGR NM_001034853.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: -1.23

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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 0.328 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38286674-CCT-C is Pathogenic according to our data. Variant chrX-38286674-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 438144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38286674-CCT-C is described in Lovd as [Pathogenic]. Variant chrX-38286674-CCT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.2323_2324del	p.Arg775GlufsTer59	frameshift_variant	15/15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.2323_2324del	p.Arg775GlufsTer59	frameshift_variant	15/15		NM_001034853.2	ENSP00000495537	A2

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD4 exome AF: 9.52e-7 AC: 1 AN: 1050521 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 342721

Gnomad4 AFR exome AF: 0.0000403

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 12

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 23, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2022	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 378 amino acids are lost and replaced with 58 incorrect amino acids; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28041643, 11992260, 31054281, 34390733) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Retinitis pigmentosa 3 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

-

- -

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

This sequence change creates a premature translational stop signal (p.Arg775Glufs*59) in the RPGR (ORF15) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 378 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 individuals with retinitis pigmentosa (PMID: 11992260, 23950152, 28041643, 31054281, 32702353). This variant is also known as c.571-2del. ClinVar contains an entry for this variant (Variation ID: 438144). For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 03, 2019

- -

Retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 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: rs1555961832; hg19: chrX-38145927;