rs62638634

Positions:

• chrX-38322921-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001034853.2(RPGR):​c.179G>T​(p.Gly60Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.52

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-38322921-C-A is Pathogenic according to our data. Variant chrX-38322921-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 9902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38322921-C-A is described in Lovd as [Pathogenic]. Variant chrX-38322921-C-A is described in Lovd as [Pathogenic]. Variant chrX-38322921-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.179G>T	p.Gly60Val	missense_variant	3/15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.179G>T	p.Gly60Val	missense_variant	3/15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-343200C>A		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2025	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23536988, 10937588, 28559085, 10958647, 19815619, 20631154, 23213406, 38586605, 34985506, 9399904, 9855162) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 16, 2019	The RPGR c.179G>T; p.Gly60Val variant (rs62638634) has been reported in several individuals with X-linked retinitis pigmentosa (Buraczynska 1997, Sharon 2000, Stone 2017) and has been reported to segregate with disease in at least one family (Fishman 1998). The variant is reported in the ClinVar database (Variation ID: 9902) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 60 is highly conserved, computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious, and structural analysis predicts this amino acid is critical in protein function and the variant causes reduced protein interaction (Patil 2012). Considering available information, this variant is classified as pathogenic. References: Buraczynska M et al. Spectrum of mutations in the RPGR gene that are identified in 20% of families with X-linked retinitis pigmentosa. Am J Hum Genet. 1997 Dec;61(6):1287-92. Fishman GA et al. X-linked retinitis pigmentosa in two families with a missense mutation in the RPGR gene and putative change of glycine to valine at codon 60. Ophthalmology. 1998 Dec;105(12):2286-96. Patil H et al. Structural and functional plasticity of subcellular tethering, targeting and processing of RPGRIP1 by RPGR isoforms. Biol Open. 2012 Feb 15;1(2):140-60. Sharon D et al. X-linked retinitis pigmentosa: mutation spectrum of the RPGR and RP2 genes and correlation with visual function. Invest Ophthalmol Vis Sci. 2000 Aug;41(9):2712-21. Stone EM et al. Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. Ophthalmology. 2017 Sep;124(9):1314-1331. -
not provided, no classification provided	literature only	Retina International	-	- -

RPGR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2024

The RPGR c.179G>T variant is predicted to result in the amino acid substitution p.Gly60Val. This variant has been reported in individuals with retinitis pigmentosa (Buraczynska et al. 1997. PubMedID: 9399904; Sharon et al. 2003. PubMed ID: 14564670; Table S3, Tuupanen et al. 2022. PubMed ID: 34985506). An in silico functional study suggests this variant causes misfolding of a particular domain of the protein (Patil et al. 2012. PubMed ID: 23213406). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/9902/). Given the evidence, we interpret this variant as pathogenic. -

Retinitis pigmentosa 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1998

- -

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RPGR protein function. ClinVar contains an entry for this variant (Variation ID: 9902). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 9399904, 9855162, 10937588). 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 replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 60 of the RPGR protein (p.Gly60Val). Experimental studies have shown that this missense change does not substantially affect RPGR function (PMID: 19815619, 20631154). For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;.;D;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;.;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.5	H;H;H;.;H;H;H;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-8.0	D;.;D;.;.;.;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;D;.;.;.;D;.
Polyphen		1.0	D;D;.;.;.;.;.;.
Vest4		0.93
MutPred		0.90		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		5.9
Varity_R		1.0
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs62638634; hg19: chrX-38182174;