rs869320726

Variant summary

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

The NM_006269.2(RP1):​c.2285_2289delTAAAT​(p.Leu762TyrfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RP1
NM_006269.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.46
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]

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 80 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-54626161-ATAAAT-A is Pathogenic according to our data. Variant chr8-54626161-ATAAAT-A is described in ClinVar as [Pathogenic]. Clinvar id is 5966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-54626161-ATAAAT-A is described in Lovd as [Pathogenic]. Variant chr8-54626161-ATAAAT-A is described in Lovd as [Likely_pathogenic]. Variant chr8-54626161-ATAAAT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RP1NM_006269.2 linkc.2285_2289delTAAAT p.Leu762TyrfsTer17 frameshift_variant Exon 4 of 4 ENST00000220676.2 NP_006260.1 P56715

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RP1ENST00000220676.2 linkc.2285_2289delTAAAT p.Leu762TyrfsTer17 frameshift_variant Exon 4 of 4 1 NM_006269.2 ENSP00000220676.1 P56715
RP1ENST00000637698.1 linkc.787+3879_787+3883delTAAAT intron_variant Intron 3 of 28 5 ENSP00000490104.1 A0A1B0GUH0
RP1ENST00000636932.1 linkc.787+3879_787+3883delTAAAT intron_variant Intron 3 of 22 5 ENSP00000489857.1 A0A1B0GTV9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460156
Hom.:
0
AF XY:
0.00000138
AC XY:
1
AN XY:
726362
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 13, 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.Leu762Tyrfs*17) in the RP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1395 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 (PMID: 10391211, 29843741). It has also been observed to segregate with disease in related individuals. This variant is also known as Leu762(5-bp del). ClinVar contains an entry for this variant (Variation ID: 5966). 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. -

-
Clinical Genetics, Academic Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Retinal dystrophy Pathogenic:2
Jan 01, 2023
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 21, 2018
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Retinitis pigmentosa 1 Pathogenic:1
Jul 01, 1999
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Retinitis pigmentosa Pathogenic:1
Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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.

Other links and lift over

dbSNP: rs869320726; hg19: chr8-55538721; API