rs758109813
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001142800.2(EYS):c.6794del(p.Pro2265GlnfsTer46) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,551,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P2265P) 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.6794del | p.Pro2265GlnfsTer46 | frameshift_variant | 34/43 | ENST00000503581.6 | |
LOC107986608 | XR_007059629.1 | n.317-22271del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.6794del | p.Pro2265GlnfsTer46 | frameshift_variant | 34/43 | 5 | NM_001142800.2 | A2 | |
EYS | ENST00000370621.7 | c.6794del | p.Pro2265GlnfsTer46 | frameshift_variant | 34/44 | 1 | P2 | ||
EYS | ENST00000398580.3 | c.108del | p.Pro37GlnfsTer46 | frameshift_variant | 2/10 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000631 AC: 96AN: 152234Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000184 AC: 29AN: 157910Hom.: 0 AF XY: 0.000132 AC XY: 11AN XY: 83396
GnomAD4 exome AF: 0.0000636 AC: 89AN: 1399528Hom.: 0 Cov.: 30 AF XY: 0.0000565 AC XY: 39AN XY: 690258
GnomAD4 genome ? AF: 0.000637 AC: 97AN: 152352Hom.: 0 Cov.: 32 AF XY: 0.000644 AC XY: 48AN XY: 74494
ClinVar
Submissions by phenotype
Retinitis pigmentosa 25 Pathogenic:5
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The EYS c.6794del 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, PS1. Based on this evidence we have classified this variant as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 25, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000275, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000281325, PMID:20333770). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 27, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 03, 2017 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2021 | 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: 20537394, 32795431, 20333770, 25412400, 29550188, 32141364, 31589614) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 12, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.Pro2265Glnfs*46) 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 (rs758109813, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 25412400, 29550188). ClinVar contains an entry for this variant (Variation ID: 281325). For these reasons, this variant has been classified as Pathogenic. - |
Retinitis pigmentosa Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | research | Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel | Jul 24, 2023 | Clinical significance based on ACMG v2.0 - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 11, 2024 | Variant summary: EYS c.6794delC (p.Pro2265GlnfsX46) 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. The variant allele was found at a frequency of 0.00018 in 157910 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.00018 vs 0.0034), allowing no conclusion about variant significance. c.6794delC has been reported in the literature in individuals affected with Retinitis Pigmentosa (e.g. Consugar_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 281325). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jan 22, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at