rs752953889

Variant summary

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

The NM_001142800.2(EYS):​c.6714delT​(p.Ile2239SerfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000522 in 1,551,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

EYS
NM_001142800.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: -0.313
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 6-64066348-TA-T is Pathogenic according to our data. Variant chr6-64066348-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 357699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-64066348-TA-T is described in Lovd as [Pathogenic]. Variant chr6-64066348-TA-T is described in Lovd as [Pathogenic]. Variant chr6-64066348-TA-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EYSNM_001142800.2 linkc.6714delT p.Ile2239SerfsTer17 frameshift_variant Exon 33 of 43 ENST00000503581.6 NP_001136272.1 Q5T1H1-1
EYSNM_001292009.2 linkc.6714delT p.Ile2239SerfsTer17 frameshift_variant Exon 33 of 44 NP_001278938.1 Q5T1H1-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EYSENST00000503581.6 linkc.6714delT p.Ile2239SerfsTer17 frameshift_variant Exon 33 of 43 5 NM_001142800.2 ENSP00000424243.1 Q5T1H1-1
EYSENST00000370621.7 linkc.6714delT p.Ile2239SerfsTer17 frameshift_variant Exon 33 of 44 1 ENSP00000359655.3 Q5T1H1-3
EYSENST00000398580.3 linkc.27delT p.Ile10fs frameshift_variant Exon 1 of 10 5 ENSP00000381585.3 H0Y3Q4

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152140
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000381
AC:
6
AN:
157482
Hom.:
0
AF XY:
0.0000241
AC XY:
2
AN XY:
82906
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000408
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000924
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000651
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000543
AC:
76
AN:
1398802
Hom.:
0
Cov.:
30
AF XY:
0.0000580
AC XY:
40
AN XY:
689780
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000282
Gnomad4 ASJ exome
AF:
0.0000795
Gnomad4 EAS exome
AF:
0.0000280
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000640
Gnomad4 OTH exome
AF:
0.0000516
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152258
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000453

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:21
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinitis pigmentosa 25 Pathogenic:9
Jun 03, 2019
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 13, 2016
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 08, 2021
Ocular Genomics Institute, Massachusetts Eye and Ear
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

The EYS c.6714del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3_strong. Based on this evidence we have classified this variant as Pathogenic. -

Jun 23, 2022
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 01, 2016
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 09, 2017
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 17, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2008
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Dec 23, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:4
Oct 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

EYS: PVS1, PM2, PS4:Moderate -

Oct 29, 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.Ile2239Serfs*17) 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 (rs752953889, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 18976725, 21069908, 26667666, 29550188). This variant is also known as p.Pro2238ProfsX16. ClinVar contains an entry for this variant (Variation ID: 357699). For these reasons, this variant has been classified as Pathogenic. -

Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 12, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32218477, 34426522, 31589614, 32037395, 31816670, 34906470, 37643323, 29550188, 25268133, 31964843, 36284460, 37322672, 36819107, 26667666, 25999674, 34662339, 25494902, 21069908, 33576794, 31074760, 34315337, 32531858, 32036094, 18976725) -

Retinitis pigmentosa Pathogenic:4
Aug 28, 2016
Illumina Laboratory Services, Illumina
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The EYS c.6714delT (p.Ile2239SerfsTer17) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Ile2239SerfsTer17 variant has been reported in a total of four individuals with autosomal recessive retinitis pigmentosa, including two homozygotes and two compound heterozygotes (Collin et al. 2008; Barragan et al. 2010; Katagiri et al. 2014; Ge et al. 2015). The variant was absent from the 1051 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. The Ile2239 residue is highly conserved. Based on the evidence from the literature and due to the potential impact of frameshift variants, the p.Ile2239SerfsTer17 variant is classified as likely pathogenic for the autosomal recessive form of retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Dec 13, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: EYS c.6714delT (p.Ile2239SerfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. At least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.8e-05 in 157482 control chromosomes (gnomAD). c.6714delT has been reported in the literature as a biallelic genotype in multiple individuals affected with Retinitis Pigmentosa and has been shown to segregate with the disease phenotype in at least one family (e.g. Collin_2008, Barragan_2010, Weisschuh_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fourteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as either pathogenic (n= 13) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

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.Ile2239SerfsTer17 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, PP5. 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. -

Apr 01, 2018
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Retinal dystrophy Pathogenic:3
Jul 30, 2019
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2023
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

Autosomal recessive retinitis pigmentosa Pathogenic:1
Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs752953889; hg19: chr6-64776241; API