rs104894927

Variant names:

• chrX-46853731-C-T
• rs104894927
• NM_006915.3:c.358C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006915.3(RP2):​c.358C>T​(p.Arg120*) variant causes a stop gained change involving the alteration of a non-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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: RP2 NM_006915.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.829
• Publications: 40 publications found

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]

RP2 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 2

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• RP2-related retinopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-46853731-C-T is Pathogenic according to our data. Variant chrX-46853731-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP2	NM_006915.3	c.358C>T	p.Arg120*	stop_gained	Exon 2 of 5	ENST00000218340.4	NP_008846.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RP2	ENST00000218340.4	c.358C>T	p.Arg120*	stop_gained	Exon 2 of 5	1	NM_006915.3	ENSP00000218340.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 2 Pathogenic:3

Jun 03, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 10, 2016

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Retinal dystrophy Pathogenic:3

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 01, 2019

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 11, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa Pathogenic:3

Jan 24, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RP2 c.358C>T (p.Arg120X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position are classified as pathogenic in ClinVar. The variant was absent in 183442 control chromosomes. c.358C>T has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa, X-Linked with evidence of cosegregation with disease within families (Hardcastle_1999, Jin_2006, Sharon_2019). These data indicate that the variant is very likely to be associated with disease. Lymphoblastoid cells from male patients with the variant have been reported to show greatly reduced RP2 mRNA expression and absent RP2 protein (Grayson_2002). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:2

Jan 20, 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.Arg120*) in the RP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RP2 are known to be pathogenic (PMID: 11992260, 20625056). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with X-linked retinitis pigmentosa (PMID: 10053026, 11262649, 25097241). ClinVar contains an entry for this variant (Variation ID: 10551). For these reasons, this variant has been classified as Pathogenic. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.78	D
PhyloP100		0.83
Vest4		0.98
GERP RS		1.4
Mutation Taster		=4/196	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894927; hg19: chrX-46713166; COSMIC: COSV54463407;