GeneBe

rs61751266

Variant names:

Variant summary

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

The NM_020366.4(RPGRIP1):​c.1107delA​(p.Glu370AsnfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000411 in 1,458,418 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RPGRIP1
NM_020366.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 4.34
Variant links:
Genes affected
RPGRIP1 (HGNC:13436): (RPGR interacting protein 1) This gene encodes a photoreceptor protein that interacts with retinitis pigmentosa GTPase regulator protein and is a key component of cone and rod photoreceptor cells. Mutations in this gene lead to autosomal recessive congenital blindness. [provided by RefSeq, Oct 2008]

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-21312457-GA-G is Pathogenic according to our data. Variant chr14-21312457-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 99809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-21312457-GA-G is described in Lovd as [Pathogenic]. Variant chr14-21312457-GA-G is described in Lovd as [Likely_pathogenic]. Variant chr14-21312457-GA-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RPGRIP1NM_020366.4 linkc.1107delA p.Glu370AsnfsTer5 frameshift_variant Exon 10 of 25 ENST00000400017.7 NP_065099.3 Q96KN7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPGRIP1ENST00000400017.7 linkc.1107delA p.Glu370AsnfsTer5 frameshift_variant Exon 10 of 25 1 NM_020366.4 ENSP00000382895.2 Q96KN7-1
RPGRIP1ENST00000557771.5 linkc.1026delA p.Glu343AsnfsTer5 frameshift_variant Exon 9 of 24 5 ENSP00000451219.1 G3V3F7
RPGRIP1ENST00000556336.5 linkc.1026delA p.Glu343AsnfsTer5 frameshift_variant Exon 9 of 21 5 ENSP00000450445.1 G3V236

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1458418
Hom.:
0
Cov.:
28
AF XY:
0.00000551
AC XY:
4
AN XY:
725500
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:15Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Leber congenital amaurosis 6 Pathogenic:10
Sep 26, 2019
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 22, 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: 0.006%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.90). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000436090 /PMID: 28041643 /3billion dataset).A different missense change at the same codon (p.Gly780Ser) has been reported to be associated with OCA2 related disorder (PMID: 32741191). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

-
Laboratory of Genetics in Ophthalmology, Institut Imagine
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Mar 26, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 07, 2020
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 07, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 01, 2001
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

-
Centogene AG - the Rare Disease Company
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 23, 2021
DBGen Ocular Genomics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 13, 2021
Breakthrough Genomics, Breakthrough Genomics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has been observed in homozygous state in multiple individuals with a clinical diagnosis of Leber congenital amaurosis [PMID: 30202406, 20079931, 24997176] and it was previously reported as recurrent variant (represented as c.1007delA (p.Glu370Asnfs*5) in the article [PMID: 24997176]. -

Cone-rod dystrophy 13 Pathogenic:2
Nov 07, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 04, 2024
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

PVS1, PM2, PP4 -

not provided Pathogenic:1Other:1
Feb 03, 2021
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Retina International
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 Pathogenic:1
Aug 27, 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.Glu370Asnfs*5) in the RPGRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPGRIP1 are known to be pathogenic (PMID: 11528500, 23105016). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Leber congenital amaurosis (PMID: 11283794, 20079931, 24997176, 30202406). This variant is also known as Lys342(1-bp del). ClinVar contains an entry for this variant (Variation ID: 99809). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Leber congenital amaurosis Pathogenic:1
Dec 13, 2017
Molecular Genetics Laboratory, Institute for Ophthalmic Research
Significance: Pathogenic
Review Status: no assertion criteria provided
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.

Other links and lift over

dbSNP: rs61751266; hg19: chr14-21780616; API