chr8-54628077-TG-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.4196delG(p.Cys1399LeufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

RP1
NM_006269.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.139

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 36 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-54628077-TG-T is Pathogenic according to our data. Variant chr8-54628077-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-54628077-TG-T is described in Lovd as [Pathogenic]. Variant chr8-54628077-TG-T is described in Lovd as [Likely_pathogenic]. Variant chr8-54628077-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP1	NM_006269.2 link	c.4196delG	p.Cys1399LeufsTer5	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.4196delG	p.Cys1399LeufsTer5	frameshift_variant	Exon 4 of 4	1	NM_006269.2	ENSP00000220676.1	P56715
RP1	ENST00000637698.1 link	c.787+5790delG		intron_variant	Intron 3 of 28	5		ENSP00000490104.1	A0A1B0GUH0
RP1	ENST00000636932.1 link	c.787+5790delG		intron_variant	Intron 3 of 22	5		ENSP00000489857.1	A0A1B0GTV9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250622

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

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:

0.00000479

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 1

Pathogenic:2

Nov 21, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25097241, 31253780). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000225457 /PMID: 25097241 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

not provided

Pathogenic:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 225457). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive retinitis pigmentosa (PMID: 25097241, 29641573, 31253780). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs762951570, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Cys1399Leufs*5) in the RP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 758 amino acid(s) of the RP1 protein. -

Retinal dystrophy

Pathogenic:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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