rs199740930
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePP3_StrongPP5_Very_Strong
The NM_001142800.2(EYS):c.2137+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.000358 in 1,531,944 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00036 ( 4 hom. )
Consequence
EYS
NM_001142800.2 splice_donor
NM_001142800.2 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.27
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.011976683 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6, offset of -36, new splice context is: ctgGTaatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 6-65057613-C-T is Pathogenic according to our data. Variant chr6-65057613-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-65057613-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EYS | NM_001142800.2 | c.2137+1G>A | splice_donor_variant | ENST00000503581.6 | |||
EYS | NM_001292009.2 | c.2137+1G>A | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYS | ENST00000503581.6 | c.2137+1G>A | splice_donor_variant | 5 | NM_001142800.2 | A2 | |||
EYS | ENST00000370621.7 | c.2137+1G>A | splice_donor_variant | 1 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000355 AC: 54AN: 152010Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000743 AC: 116AN: 156184Hom.: 1 AF XY: 0.000689 AC XY: 57AN XY: 82776
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GnomAD4 exome AF: 0.000358 AC: 494AN: 1379816Hom.: 4 Cov.: 28 AF XY: 0.000362 AC XY: 247AN XY: 681964
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:18Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Retinitis pigmentosa 25 Pathogenic:9Uncertain:1
Uncertain significance, flagged submission | clinical testing | Blueprint Genetics | Aug 01, 2019 | We have identified this variant in >10 individuals with a retinal dystrophy clinical indication. The variant was only seen in the heterozygous state in these individuals. Further, nearly half had a LP/P variant in another gene which explained their phenotype. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Dec 21, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 25 (MIM#602772). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 123 heterozygotes, 1 homozygote). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple retinitis pigmentosa individuals, including homozygotes, and is classified as likely pathogenic/pathogenic by diagnostic laboratories in ClinVar (PMIDs: 28704921, 32728228). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Likely pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Oct 11, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 11, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Jun 29, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | May 09, 2022 | - - |
Pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NG_023443.2(NM_001142800.1):c.2137+1G>A in the EYS gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This sequence change affects a donor splice site in intron 13 of the EYS gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been observed as homozygous in an individual affected with retinitis pigmentosa (PMID: 28704921). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3_Supporting; PP4. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 02, 2023 | - - |
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change affects a donor splice site in intron 13 of the EYS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is present in population databases (rs199740930, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with retinitis pigmentosa (PMID: 28704921, 30718709, 33576794). ClinVar contains an entry for this variant (Variation ID: 421249). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 01, 2022 | Observed with a second EYS variant, phase unknown, in patients with retinitis pigmentosa in literature; however, these patients had variants in other genes that may have also contributed to the phenotype (Jespersgaard et al., 2019; Cundy et al., 2021; Colombo et al., 2021); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30718709, 28704921, 34426522, 31589614, 31456290, 31980526, 32552793, 33576794, 32728228) - |
Retinitis pigmentosa Pathogenic:4
Likely pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 07, 2022 | Variant summary: EYS c.2137+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 0.00074 in 156184 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.00074 vs 0.0034). The variant, c.2137+1G>A, has been reported in the literature in the homozygous and compound heterozygous state in individuals affected with Retinitis Pigmentosa (example McGuigan_2017, Jespersgaard_2019, Sharon_2020, Colombo_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. There have been 13 assessments for this variant submitted to ClinVar after 2014. Five classified the variant as pathogenic, seven as likely pathogenic, and one as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
EYS-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 29, 2024 | The EYS c.2137+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the homozygous state or with a second potentially causative variant in several individuals with suspected retinitis pigmentosa (McGuigan et al. 2017. PubMed ID: 28704921; Cundy et al. 2020. PubMed ID: 32728228; Colombo et al. 2021. PubMed ID: 33576794). This variant is reported in 0.89% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygous individual. Variants that disrupt the consensus splice donor site in EYS are expected to be pathogenic. In ClinVar, this variant has been interpreted as uncertain, likely pathogenic, or pathogenic by outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/421249/?new_evidence=true). We classify this variant as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
GERP RS
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 37
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at