rs758109813
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001142800.2(EYS):c.6794delC(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
Publications
- EYS-related retinopathyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- retinitis pigmentosaInheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
- retinitis pigmentosa 25Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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EYS | ENST00000503581.6 | c.6794delC | p.Pro2265GlnfsTer46 | frameshift_variant | Exon 34 of 43 | 5 | NM_001142800.2 | ENSP00000424243.1 | ||
EYS | ENST00000370621.7 | c.6794delC | p.Pro2265GlnfsTer46 | frameshift_variant | Exon 34 of 44 | 1 | ENSP00000359655.3 | |||
EYS | ENST00000398580.3 | c.107delC | p.Pro36fs | frameshift_variant | Exon 2 of 10 | 5 | ENSP00000381585.3 |
Frequencies
GnomAD3 genomes AF: 0.000631 AC: 96AN: 152234Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000184 AC: 29AN: 157910 AF XY: 0.000132 show subpopulations
GnomAD4 exome AF: 0.0000636 AC: 89AN: 1399528Hom.: 0 Cov.: 30 AF XY: 0.0000565 AC XY: 39AN XY: 690258 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000637 AC: 97AN: 152352Hom.: 0 Cov.: 32 AF XY: 0.000644 AC XY: 48AN XY: 74494 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Retinitis pigmentosa 25 Pathogenic:6
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
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. -
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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. -
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not provided Pathogenic:3
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. -
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) -
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Retinitis pigmentosa Pathogenic:3
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. -
Clinical significance based on ACMG v2.0 -
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EYS-related disorder Pathogenic:1
The EYS c.6794delC variant is predicted to result in a frameshift and premature protein termination (p.Pro2265Glnfs*46). This variant has been reported in multiple individuals with retinitis pigmentosa (Audo et al. 2010. PubMed ID: 20333770; Supplementary Table, Zanolli et al. 2020. PubMed ID: 32141364; Georgiou et al. 2020. PubMed ID: 32795431). This variant is reported in 0.29% of alleles in individuals of African descent in gnomAD, indicating it is relatively common. Frameshift variants in EYS are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic. -
Retinal dystrophy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at