rs794727631
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001142800.2(EYS):c.490C>T(p.Arg164*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,940 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R164R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001142800.2 stop_gained
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
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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EYS | NM_001142800.2 | c.490C>T | p.Arg164* | stop_gained | Exon 4 of 43 | ENST00000503581.6 | NP_001136272.1 | |
EYS | NM_001292009.2 | c.490C>T | p.Arg164* | stop_gained | Exon 4 of 44 | NP_001278938.1 | ||
EYS | NM_001142801.2 | c.490C>T | p.Arg164* | stop_gained | Exon 4 of 12 | NP_001136273.1 | ||
EYS | NM_198283.2 | c.490C>T | p.Arg164* | stop_gained | Exon 3 of 10 | NP_938024.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152082Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000796 AC: 2AN: 251220 AF XY: 0.0000147 show subpopulations
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727224 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152082Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74302 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
Age Distribution
ClinVar
Submissions by phenotype
Retinitis pigmentosa 25 Pathogenic:6
The EYS c.490C>T (p.Arg164Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The variant has been reported in a compound heterozygous state in at least five individuals, including two siblings, affected with retinitis pigmentosa (O'Sullivan et al. 2012; Chen et al. 2015; McGuigan et al. 2017). The variant is reported at a frequency of 0.000008 in the Total population of the Genome Aggregation database (version 2.1.1), though this is based on only two occurrences in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence, the p.Arg164Ter variant is classified as pathogenic for autosomal recessive retinitis pigmentosa. -
Stop-gained (nonsense): 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). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000197186, PMID:22581970). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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not provided Pathogenic:3
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This sequence change creates a premature translational stop signal (p.Arg164*) 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 (rs794727631, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with retinitis pigmentosa (PMID: 22581970, 25753737). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197186). For these reasons, this variant has been classified as Pathogenic. -
Retinitis pigmentosa Pathogenic:2
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ACMG/AMP guidelines: PM2, PVS1, PP1, PM3_1 -
Retinal dystrophy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at