rs750542962

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.1719_1723delCTCAA(p.Ser574CysfsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000105 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

RP1
NM_006269.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.87

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 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 119 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-54625598-TAACTC-T is Pathogenic according to our data. Variant chr8-54625598-TAACTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-54625598-TAACTC-T is described in Lovd as [Likely_pathogenic]. Variant chr8-54625598-TAACTC-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.1719_1723delCTCAA	p.Ser574CysfsTer7	frameshift_variant	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.1719_1723delCTCAA	p.Ser574CysfsTer7	frameshift_variant	Exon 4 of 4	1	NM_006269.2	ENSP00000220676.1	P56715
RP1	ENST00000637698.1 link	c.787+3313_787+3317delCTCAA		intron_variant	Intron 3 of 28	5		ENSP00000490104.1	A0A1B0GUH0
RP1	ENST00000636932.1 link	c.787+3313_787+3317delCTCAA		intron_variant	Intron 3 of 22	5		ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251222

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461808

Hom.:

AF XY:

0.00000550

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

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

AF:

0.0000394

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000718

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Dec 24, 2019

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 1583 amino acids are lost and replaced with 6 incorrect amino acids; This variant is associated with the following publications: (PMID: 25692139, 26355662) -

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 24, 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.Ser574Cysfs*7) in the RP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1583 amino acid(s) of the RP1 protein. This variant is present in population databases (rs750542962, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive or sporadic retinitis pigmentosa (PMID: 25692139, 26355662; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 191341). 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. -

Autosomal recessive retinitis pigmentosa

Pathogenic:1

Sep 10, 2015

Faculty of Health Sciences, Beirut Arab University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Retinal dystrophy

Pathogenic:1

Aug 06, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Pathogenic:1

Jul 24, 2023

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Clinical significance based on ACMG v2.0 -

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.

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