chrX-46853725-C-T

Position:

• chrX-46853725-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000218340.4(RP2):​c.352C>T​(p.Arg118Cys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R118G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: RP2 ENST00000218340.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.45

Genes affected

RP2 (HGNC:10274): (RP2 activator of ARL3 GTPase) The RP2 locus has been implicated as one cause of X-linked retinitis pigmentosa. The predicted gene product shows homology with human cofactor C, a protein involved in the ultimate step of beta-tubulin folding. Progressive retinal degeneration may therefore be due to the accumulation of incorrectly-folded photoreceptor or neuron-specific tubulin isoforms followed by progressive cell death [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a mutagenesis_site Reduces affinity and GTP-hydrolysis rate for mouse ARL3. (size 0) in uniprot entity XRP2_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in ENST00000218340.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-46853726-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-46853725-C-T is Pathogenic according to our data. Variant chrX-46853725-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 437944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-46853725-C-T is described in Lovd as [Pathogenic]. Variant chrX-46853725-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-46853725-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RP2	NM_006915.3	c.352C>T	p.Arg118Cys	missense_variant	2/5	ENST00000218340.4	NP_008846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RP2	ENST00000218340.4	c.352C>T	p.Arg118Cys	missense_variant	2/5	1	NM_006915.3	ENSP00000218340	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 02, 2022	ClinVar contains an entry for this variant (Variation ID: 437944). This missense change has been observed in individuals with inherited retinal disease (PMID: 12657579, 28041643, 31456290). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 118 of the RP2 protein (p.Arg118Cys). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg118 amino acid residue in RP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9697692, 12657579, 20021257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change does not substantially affect RP2 function (PMID: 28209709). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Retinal dystrophy Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2017	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 02, 2019	- -

X-linked retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Faculty of Health Sciences, Beirut Arab University

Sep 10, 2015

- -

Retinitis pigmentosa 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Sep 01, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.96). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12657579 , 28041643 , 31456290). A different missense change at the same codon (p.Arg118His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010546). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Retinitis pigmentosa Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.98		Loss of MoRF binding (P = 0.0658);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.98
gMVP		0.93

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: rs1556318633; hg19: chrX-46713160; COSMIC: COSV54460861;