rs1554519422

chr8-54625148-TGCTAGTTGGGAGAATGCTACTGTGGACACAGATATCATCCAGGGAACTCAAGACCAAGCAAAGCATCGTTTTTATAGGCCCCCTACACCTGGACTAAGAAGAGTGAGACAAAAGAAATCTGTGATTGGCAGTGTGACCTTAGTATCTGAAACTGAGGTTCAAGAGAAAATGATTGGACAGTTTTCATATAGTGAAGAAAGGGAAAGTGGGGAAAACAAGTCTGAGTATCACATGTTTACACATTCTTGCAGTAAAATGTCATCAGTATCTAACAAACCAGTACTTGTTCAGATCAATAACAATGATCAAATGGAGGAGTCATCATTAGAAAGAAAAAAGGAAAACAGTCTGCTTAAGTCAAGTGCAATAAGTGCTGGTGTTATAGAAATT-TA

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_006269.2(RP1):c.1267_1656delinsA(p.Ala423AsnfsTer11) variant causes a frameshift change. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A423A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RP1 NM_006269.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.58

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 Likely_pathogenic. Variant got 9 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 253 pathogenic variants in the truncated region.
• PP5: Variant 8-54625149-GCTAGTTGGGAGAATGCTACTGTGGACACAGATATCATCCAGGGAACTCAAGACCAAGCAAAGCATCGTTTTTATAGGCCCCCTACACCTGGACTAAGAAGAGTGAGACAAAAGAAATCTGTGATTGGCAGTGTGACCTTAGTATCTGAAACTGAGGTTCAAGAGAAAATGATTGGACAGTTTTCATATAGTGAAGAAAGGGAAAGTGGGGAAAACAAGTCTGAGTATCACATGTTTACACATTCTTGCAGTAAAATGTCATCAGTATCTAACAAACCAGTACTTGTTCAGATCAATAACAATGATCAAATGGAGGAGTCATCATTAGAAAGAAAAAAGGAAAACAGTCTGCTTAAGTCAAGTGCAATAAGTGCTGGTGTTATAGAAATT-A is Pathogenic according to our data. Variant chr8-54625149-GCTAGTTGGGAGAATGCTACTGTGGACACAGATATCATCCAGGGAACTCAAGACCAAGCAAAGCATCGTTTTTATAGGCCCCCTACACCTGGACTAAGAAGAGTGAGACAAAAGAAATCTGTGATTGGCAGTGTGACCTTAGTATCTGAAACTGAGGTTCAAGAGAAAATGATTGGACAGTTTTCATATAGTGAAGAAAGGGAAAGTGGGGAAAACAAGTCTGAGTATCACATGTTTACACATTCTTGCAGTAAAATGTCATCAGTATCTAACAAACCAGTACTTGTTCAGATCAATAACAATGATCAAATGGAGGAGTCATCATTAGAAAGAAAAAAGGAAAACAGTCTGCTTAAGTCAAGTGCAATAAGTGCTGGTGTTATAGAAATT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547180.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RP1	NM_006269.2	c.1267_1656delinsA	p.Ala423AsnfsTer11	frameshift_variant	4/4	ENST00000220676.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RP1	ENST00000220676.2	c.1267_1656delinsA	p.Ala423AsnfsTer11	frameshift_variant	4/4	1	NM_006269.2
RP1	ENST00000636932.1	c.787+2861_787+3250delinsA		intron_variant		5
RP1	ENST00000637698.1	c.787+2861_787+3250delinsA		intron_variant		5		P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2022

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. ClinVar contains an entry for this variant (Variation ID: 547180). This variant has not been reported in the literature in individuals affected with RP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala423Asnfs*11) in the RP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1734 amino acid(s) of the RP1 protein. -

Leber congenital amaurosis 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Australian Inherited Retinal Disease Registry & DNA Bank, Sir Charles Gairdner Hospital

Nov 30, 2017

Detected in an unaffected mother, and in an affected individual with another genetic cause for disease; not considered primary cause of disease -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554519422; hg19: chr8-55537709;