rs1449723475

chr8-54626489-G-GA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006269.2(RP1):c.2613dup(p.Arg872ThrfsTer2) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000274 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RP1 NM_006269.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.42

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]

ACMG classification

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 124 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-54626489-G-GA is Pathogenic according to our data. Variant chr8-54626489-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 437955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RP1	NM_006269.2	c.2613dup	p.Arg872ThrfsTer2	frameshift_variant	4/4	ENST00000220676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RP1	ENST00000220676.2	c.2613dup	p.Arg872ThrfsTer2	frameshift_variant	4/4	1	NM_006269.2
RP1	ENST00000636932.1	c.787+4207dup		intron_variant		5
RP1	ENST00000637698.1	c.787+4207dup		intron_variant		5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461660 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2023	This sequence change creates a premature translational stop signal (p.Arg872Thrfs*2) in the RP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1285 amino acid(s) of the RP1 protein. This variant is present in population databases (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with autosomal dominant retinitis pigmentosa (RP) (PMID: 11095597, 27391102, 28041643). It has also been observed to segregate with disease in related individuals. This variant is also known as c.2608-2609insA. ClinVar contains an entry for this variant (Variation ID: 437955). 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. -

Retinal dystrophy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 27, 2018	- -
Likely pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

Retinitis pigmentosa Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Jan 09, 2020	- -
Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

Retinitis pigmentosa 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Molecular Genetics, University of Zurich

Jan 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1449723475; hg19: chr8-55539049;