rs752953889
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001142800.2(EYS):c.6714del(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 (★★). Synonymous variant affecting the same amino acid position (i.e. P2238P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001142800.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EYS | NM_001142800.2 | c.6714del | p.Ile2239SerfsTer17 | frameshift_variant | 33/43 | ENST00000503581.6 | |
EYS | NM_001292009.2 | c.6714del | p.Ile2239SerfsTer17 | frameshift_variant | 33/44 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.6714del | p.Ile2239SerfsTer17 | frameshift_variant | 33/43 | 5 | NM_001142800.2 | A2 | |
EYS | ENST00000370621.7 | c.6714del | p.Ile2239SerfsTer17 | frameshift_variant | 33/44 | 1 | P2 | ||
EYS | ENST00000398580.3 | c.28del | p.Ile11SerfsTer17 | frameshift_variant | 1/10 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000381 AC: 6AN: 157482Hom.: 0 AF XY: 0.0000241 AC XY: 2AN XY: 82906
GnomAD4 exome AF: 0.0000543 AC: 76AN: 1398802Hom.: 0 Cov.: 30 AF XY: 0.0000580 AC XY: 40AN XY: 689780
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152258Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74456
ClinVar
Submissions by phenotype
Retinitis pigmentosa 25 Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 23, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Sep 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | May 13, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 09, 2017 | - - |
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 05, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Jun 03, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2008 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 23, 2021 | - - |
Retinitis pigmentosa Pathogenic:4
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Apr 01, 2021 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 28, 2016 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 13, 2022 | 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. - |
Pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | EYS: PVS1, PM2, PS4:Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Retinal dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 30, 2019 | - - |
Pathogenic, criteria provided, single submitter | research | Dept Of Ophthalmology, Nagoya University | Oct 01, 2023 | - - |
Autosomal recessive retinitis pigmentosa Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at