8-54625911-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_006269.2(RP1):c.2029C>T(p.Arg677*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

RP1
NM_006269.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 0.783

Variant links:

Genes affected

RP1 (HGNC:10263): (RP1 axonemal microtubule associated) This gene encodes a member of the doublecortin family. The protein encoded by this gene contains two doublecortin domains, which bind microtubules and regulate microtubule polymerization. The encoded protein is a photoreceptor microtubule-associated protein and is required for correct stacking of outer segment disc. This protein and the RP1L1 protein, another retinal-specific protein, play essential and synergistic roles in affecting photosensitivity and outer segment morphogenesis of rod photoreceptors. Because of its response to in vivo retinal oxygen levels, this protein was initially named ORP1 (oxygen-regulated protein-1). This protein was subsequently designated RP1 (retinitis pigmentosa 1) when it was found that mutations in this gene cause autosomal dominant retinitis pigmentosa. Mutations in this gene also cause autosomal recessive retinitis pigmentosa. Transcript variants resulted from an alternative promoter and alternative splicings have been found, which overlap the current reference sequence and has several exons upstream and downstream of the current reference sequence. However, the biological validity and full-length nature of some variants cannot be determined at this time.[provided by RefSeq, Sep 2010]

RP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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. There are 114 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-54625911-C-T is Pathogenic according to our data. Variant chr8-54625911-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-54625911-C-T is described in Lovd as [Pathogenic]. Variant chr8-54625911-C-T is described in Lovd as [Likely_pathogenic]. Variant chr8-54625911-C-T is described in Lovd as [Pathogenic]. Variant chr8-54625911-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP1	NM_006269.2 link	c.2029C>T	p.Arg677*	stop_gained	Exon 4 of 4	ENST00000220676.2	NP_006260.1	P56715

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RP1	ENST00000220676.2 link	c.2029C>T	p.Arg677*	stop_gained	Exon 4 of 4	1	NM_006269.2	ENSP00000220676.1	P56715
RP1	ENST00000637698.1 link	c.787+3623C>T		intron_variant	Intron 3 of 28	5		ENSP00000490104.1	A0A1B0GUH0
RP1	ENST00000636932.1 link	c.787+3623C>T		intron_variant	Intron 3 of 22	5		ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727092

show subpopulations

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Jul 25, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 08, 2024

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.Arg677*) in the RP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1480 amino acid(s) of the RP1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal dominant retinitis pigmentosa (adRP) (PMID: 10391211, 29847639). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5965). This variant disrupts the C-terminus of the RP1 protein. Many variants that disrupt this region have been reported in individuals with either autosomal dominant or autosomal recessive retinitis pigmentosa (PMID: 11527933, 19933189, 29425069, 30027431, 33681214). Therefore, variants that disrupt this region are expected to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Oct 29, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation, as the last 1480 amino acid(s) are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10391212, 32795431, 32193659, 8931712, 1783394, 10401003, 29425069, 29630435, 29881650, 23757202, 29847639, 30913292, 31054281, 32581362, 33576794, 33144682, 32037395, 32326409, 35886928, 28761320, 33608557, 36460718, 31213501, 36819107, 37217489, 33749171, 36284460, 37734845, 34906470, 32565670, 34073704, 35814500, 33598457, 31736247, 38219857, 12882812, 10391211) -

Retinitis pigmentosa 1

Pathogenic:4

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The RP1 c.2029C>T variant was identified in an individual with retinitis pigmentosa with a presumed dominant inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PS3, PM2, PP1. Based on this evidence we have classified this variant as Pathogenic. -

Aug 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 03, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4,PS2_MOD -

Retinal dystrophy

Pathogenic:3

Jun 24, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 01, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RP1-related disorder

Pathogenic:1

Aug 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RP1 c.2029C>T variant is predicted to result in premature protein termination (p.Arg677*). This variant has been reported many times as causative for autosomal dominant retinitis pigmentosa (see for examples: Pierce et al. 1999. PubMed ID: 10391211; Guillonneau et al. 1999. PubMed ID: 10401003; Martin-Merida et al. 2018. PubMed ID: 29847639). This variant has not been reported in a large population database, indicating it is rare. Nonsense variants in RP1 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/5965). Given all the evidence, we interpret this variant as pathogenic for autosomal dominant disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.70

Vest4

0.79

GERP RS

4.8

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over