rs200935518

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001142800.2(EYS):c.4891C>T(p.Pro1631Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,551,228 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00078 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 5 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7B:2

Conservation

PhyloP100: 1.00

Publications

8 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

EYS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012373656).

BS2

High Homozygotes in GnomAdExome4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.4891C>T	p.Pro1631Ser	missense_variant	Exon 26 of 43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_001292009.2 link	c.4891C>T	p.Pro1631Ser	missense_variant	Exon 26 of 44		NP_001278938.1	Q5T1H1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6 link	c.4891C>T	p.Pro1631Ser	missense_variant	Exon 26 of 43	5	NM_001142800.2	ENSP00000424243.1		Q5T1H1-1
EYS	ENST00000370621.7 link	c.4891C>T	p.Pro1631Ser	missense_variant	Exon 26 of 44	1		ENSP00000359655.3		Q5T1H1-3

Frequencies

GnomAD3 genomes

AF:

0.000776

AC:

118

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

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:

0.00144

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000841

AC:

129

AN:

153362

AF XY:

0.000885

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000263

Gnomad NFE exome

AF:

0.00162

Gnomad OTH exome

AF:

0.00162

GnomAD4 exome

AF:

0.00144

AC:

2017

AN:

1399030

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

959

AN XY:

690036

show subpopulations

African (AFR)

AF:

0.000127

AC:

AN:

31580

American (AMR)

AF:

0.000840

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25164

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35726

South Asian (SAS)

AF:

0.000151

AC:

AN:

79230

European-Finnish (FIN)

AF:

0.000244

AC:

AN:

49174

Middle Eastern (MID)

AF:

0.00158

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00175

AC:

1884

AN:

1078768

Other (OTH)

AF:

0.00112

AC:

AN:

57986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

115

231

346

462

577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.000775

AC:

118

AN:

152198

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41560

American (AMR)

AF:

0.000589

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00144

AC:

AN:

67978

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00132

Hom.:

Bravo

AF:

0.000903

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ExAC

AF:

0.000557

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Uncertain:4

Sep 26, 2017

Counsyl

Significance:Uncertain significance

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. -

Aug 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 18, 2021

Pars Genome Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:2

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1631 of the EYS protein (p.Pro1631Ser). This variant is present in population databases (rs200935518, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with retinal disease (PMID: 23591405, 25366773). ClinVar contains an entry for this variant (Variation ID: 554129). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:1

May 12, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: EYS c.4891C>T (p.Pro1631Ser) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00084 in 153362 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.00084 vs 0.0034), allowing no conclusion about variant significance. c.4891C>T has been observed in individual(s) affected with retinitis pigmentosa/retinal dystrophy (e.g. Neveling_2012, Glockle_2013, Messchaert_2018, Colombo_2021, Karali_2022, Mihalich_2024). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33576794, 23591405, 36460718, 29159838, 38927702, 22334370). ClinVar contains an entry for this variant (Variation ID: 554129). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Retinitis pigmentosa

Uncertain:1

Feb 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.041

.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.55

N;N

PhyloP100

1.0

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.17

N;N

REVEL

Benign

0.20

Sift

Benign

0.082

T;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.53

P;B

Vest4

0.063

MVP

0.44

MPC

0.017

ClinPred

0.042

GERP RS

1.2

Varity_R

0.051

gMVP

0.017

Mutation Taster

=73/27

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over