rs1060499783

Variant summary

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

The NM_001142800.2(EYS):​c.6976C>T​(p.Arg2326*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000839 in 1,549,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

EYS
NM_001142800.2 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 1.25
Variant links:
Genes affected
EYS (HGNC:21555): (eyes shut homolog) The product of this gene contains multiple epidermal growth factor (EGF)-like and LamG domains. The protein is expressed in the photoreceptor layer of the retina, and the gene is mutated in autosomal recessive retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 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 6-63984462-G-A is Pathogenic according to our data. Variant chr6-63984462-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-63984462-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EYSNM_001142800.2 linkc.6976C>T p.Arg2326* stop_gained Exon 35 of 43 ENST00000503581.6 NP_001136272.1 Q5T1H1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EYSENST00000503581.6 linkc.6976C>T p.Arg2326* stop_gained Exon 35 of 43 5 NM_001142800.2 ENSP00000424243.1 Q5T1H1-1
EYSENST00000370621.7 linkc.6976C>T p.Arg2326* stop_gained Exon 35 of 44 1 ENSP00000359655.3 Q5T1H1-3
EYSENST00000398580.3 linkc.289C>T p.Arg97* stop_gained Exon 3 of 10 5 ENSP00000381585.3 H0Y3Q4

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151656
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000255
AC:
4
AN:
156918
Hom.:
0
AF XY:
0.0000361
AC XY:
3
AN XY:
83004
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000810
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000439
Gnomad FIN exome
AF:
0.0000593
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000787
AC:
11
AN:
1397656
Hom.:
0
Cov.:
32
AF XY:
0.0000116
AC XY:
8
AN XY:
689412
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000561
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000631
Gnomad4 FIN exome
AF:
0.0000406
Gnomad4 NFE exome
AF:
0.00000186
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151656
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74054
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinitis pigmentosa 25 Pathogenic:4
Jul 24, 2015
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.6976C>T (p.Arg2326*) is a novel nonsense variant in the EYS gene that leads to premature truncation of the protein, causing a disorder where loss of function is a mechanism of disease. Other pathogenic nonsense variants have been described in the EYS gene in several affected individuals, linked to the disease, and reported to be in the same region as this nonsense variant (Littinik et al., 2010 and Iwanami et al., 2012). This p.Arg2326* has not been reported in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAc) and displayed a high CADD score (45). Therefore, this collective evidence supports the classification of the c.6976C>T (p.Arg2326*) as a recessive likely pathogenic variant for Retinitis Pigmentosa-25. -

Mar 10, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 14, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 14, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Retinal dystrophy Pathogenic:2
Oct 01, 2023
Dept Of Ophthalmology, Nagoya University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Jan 01, 2020
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Retinitis pigmentosa Pathogenic:2
Jun 23, 2019
Sharon lab, Hadassah-Hebrew University Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Apr 01, 2021
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

The p.Arg2326Ter variant in EYS was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3-P. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

not provided Pathogenic:1
Nov 19, 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.Arg2326*) in the EYS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is present in population databases (no rsID available, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with autosomal recessive retinitis pigmentosa (PMID: 26161267). ClinVar contains an entry for this variant (Variation ID: 402227). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
36
DANN
Uncertain
0.99
Eigen
Uncertain
0.31
Eigen_PC
Benign
0.0018
FATHMM_MKL
Benign
0.15
N
Vest4
0.97
GERP RS
4.3

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1060499783; hg19: chr6-64694355; COSMIC: COSV65462788; API