rs786205589

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1PM1PM2PP3_StrongPP5_Very_Strong

The NM_006269.2(RP1):c.607G>A(p.Gly203Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RP1
NM_006269.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.82

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PS1

Transcript NM_006269.2 (RP1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM1

In a domain Doublecortin 2 (size 79) in uniprot entity RP1_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_006269.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 8-54621573-G-A is Pathogenic according to our data. Variant chr8-54621573-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-54621573-G-A is described in Lovd as [Likely_pathogenic]. Variant chr8-54621573-G-A 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.607G>A	p.Gly203Arg	missense_variant	Exon 2 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.607G>A	p.Gly203Arg	missense_variant	Exon 2 of 4	1	NM_006269.2	ENSP00000220676.1	P56715
RP1	ENST00000637698.1 link	c.607G>A	p.Gly203Arg	missense_variant	Exon 2 of 29	5		ENSP00000490104.1	A0A1B0GUH0
RP1	ENST00000636932.1 link	c.607G>A	p.Gly203Arg	missense_variant	Exon 2 of 23	5		ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727226

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 203 of the RP1 protein (p.Gly203Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive retinitis pigmentosa (PMID: 24265693, 32587456). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 191224). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Gly203 amino acid residue in RP1. Other variant(s) that disrupt this residue have been observed in individuals with RP1-related conditions (PMID: 24938718), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

.;D;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

.;M;.

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.9

.;D;.

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

.;D;.

Sift4G

Uncertain

0.0050

.;D;.

Polyphen

1.0

.;D;.

Vest4

0.96

MutPred

0.95

Gain of MoRF binding (P = 0.0344);Gain of MoRF binding (P = 0.0344);Gain of MoRF binding (P = 0.0344);

MVP

0.98

MPC

0.22

ClinPred

1.0

GERP RS

4.4

Varity_R

0.97

gMVP

0.88

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