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

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

EYS
NM_001142800.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 1.45

Publications

5 publications found
Variant links:
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]
EYS Gene-Disease associations (from GenCC):
  • EYS-related retinopathy
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • retinitis pigmentosa
    Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
  • retinitis pigmentosa 25
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 6-63999114-TG-T is Pathogenic according to our data. Variant chr6-63999114-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 281325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EYSNM_001142800.2 linkc.6794delC p.Pro2265GlnfsTer46 frameshift_variant Exon 34 of 43 ENST00000503581.6 NP_001136272.1 Q5T1H1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EYSENST00000503581.6 linkc.6794delC p.Pro2265GlnfsTer46 frameshift_variant Exon 34 of 43 5 NM_001142800.2 ENSP00000424243.1 Q5T1H1-1
EYSENST00000370621.7 linkc.6794delC p.Pro2265GlnfsTer46 frameshift_variant Exon 34 of 44 1 ENSP00000359655.3 Q5T1H1-3
EYSENST00000398580.3 linkc.107delC p.Pro36fs frameshift_variant Exon 2 of 10 5 ENSP00000381585.3 H0Y3Q4

Frequencies

GnomAD3 genomes
AF:
0.000631
AC:
96
AN:
152234
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00227
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.000184
AC:
29
AN:
157910
AF XY:
0.000132
show subpopulations
Gnomad AFR exome
AF:
0.00320
Gnomad AMR exome
AF:
0.000121
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000636
AC:
89
AN:
1399528
Hom.:
0
Cov.:
30
AF XY:
0.0000565
AC XY:
39
AN XY:
690258
show subpopulations
African (AFR)
AF:
0.00241
AC:
76
AN:
31592
American (AMR)
AF:
0.000140
AC:
5
AN:
35706
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25178
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35724
South Asian (SAS)
AF:
0.0000126
AC:
1
AN:
79230
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49426
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5698
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1078872
Other (OTH)
AF:
0.000120
AC:
7
AN:
58102
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.473
Heterozygous variant carriers
0
5
10
14
19
24
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000637
AC:
97
AN:
152352
Hom.:
0
Cov.:
32
AF XY:
0.000644
AC XY:
48
AN XY:
74494
show subpopulations
African (AFR)
AF:
0.00228
AC:
95
AN:
41588
American (AMR)
AF:
0.0000654
AC:
1
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68036
Other (OTH)
AF:
0.000473
AC:
1
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
5
10
14
19
24
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000427
Hom.:
0
Bravo
AF:
0.000790

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Retinitis pigmentosa 25 Pathogenic:6
Nov 03, 2017
Counsyl
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

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. -

Apr 08, 2021
Ocular Genomics Institute, Massachusetts Eye and Ear
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

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. -

Jan 27, 2022
Revvity Omics, Revvity
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 03, 2022
3billion
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Mar 26, 2024
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 06, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Pathogenic:3
Dec 02, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Nov 02, 2021
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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) -

Jun 12, 2015
Eurofins Ntd Llc (ga)
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Retinitis pigmentosa Pathogenic:3
Jan 11, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Jul 24, 2023
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

Clinical significance based on ACMG v2.0 -

Sep 16, 2020
Natera, Inc.
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

EYS-related disorder Pathogenic:1
Apr 12, 2024
PreventionGenetics, part of Exact Sciences
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

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
Jan 22, 2018
Blueprint Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
1.4
Mutation Taster
=3/197
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs758109813; hg19: chr6-64709007; API