chr6-64912597-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 4P and 7B. PM1PM5BP4_ModerateBS1_SupportingBS2

The NM_001142800.2(EYS):c.2528G>A(p.Gly843Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000247 in 1,551,158 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G843R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 2 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9U:2

Conservation

PhyloP100: 6.15

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a domain EGF-like 11 (size 38) in uniprot entity EYS_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_001142800.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-64912598-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.1148926).

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000259 (363/1399086) while in subpopulation EAS AF= 0.0101 (361/35718). AF 95% confidence interval is 0.00925. There are 2 homozygotes in gnomad4_exome. There are 171 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.2528G>A	p.Gly843Glu	missense_variant	Exon 16 of 43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_001292009.2 link	c.2528G>A	p.Gly843Glu	missense_variant	Exon 16 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.2528G>A	p.Gly843Glu	missense_variant	Exon 16 of 43	5	NM_001142800.2	ENSP00000424243.1		Q5T1H1-1
EYS	ENST00000370621.7 link	c.2528G>A	p.Gly843Glu	missense_variant	Exon 16 of 44	1		ENSP00000359655.3		Q5T1H1-3

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000256

AC:

AN:

156432

Hom.:

AF XY:

0.0000241

AC XY:

AN XY:

82868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000367

Gnomad SAS 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:

0.000259

AC:

363

AN:

1399086

Hom.:

Cov.:

AF XY:

0.000248

AC XY:

171

AN XY:

690040

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.000132

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000151

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Pathogenic:5Uncertain:1

Jun 04, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

The EYS c.2528G>A 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: PM2, PM3, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance. -

Oct 17, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Predicted Consequence/Location: The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. Premature termination of the protein is a common disease-causing mechanism for this gene. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.73 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.82 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000636026 /PMID: 29785639). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 31814702). A different missense change at the same codon (p.Gly843Arg) has been reported to be associated with EYS-related disorder (ClinVar ID: VCV001213994). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:2

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 843 of the EYS protein (p.Gly843Glu). This variant is present in population databases (rs74419361, gnomAD 0.04%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 22302105, 22363543, 29785639, 31814702; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 636026). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EYS protein function. For these reasons, this variant has been classified as Pathogenic. -

Jun 26, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22302105, 29785639, 33691693, 34721897, 31253780, 31054281, 31814702, 33946315, 30718709, 33247286, 32218477, 22363543, 32079136, 36284460, 35109811, 33514863) -

Retinitis pigmentosa

Pathogenic:1Uncertain:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Apr 09, 2025

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.2528G>A (p.Gly843Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 1551158 control chromosomes, predominantly at a frequency of 0.0093 within the East Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.72 fold of the estimated maximal expected allele frequency for a pathogenic variant in EYS causing Retinitis Pigmentosa phenotype (0.0034). However, multiple studies have demonstrated that c.2528G>A is found in many more affected individuals than controls in the homozygous or compound heterozygous state who have EYS-related retinal dystrophy and/or Retinitis Pigmentosa (example, Nishiguchi_2021, Yang_2020), including multiple families where it segregated with disease. These data indicate that the variant is very likely to be associated with disease and may be a Japanese founder variant. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity in vitro (example, Nishiguchi_2021). The following publications have been ascertained in the context of this evaluation (PMID: 33514863, 32218477). ClinVar contains an entry for this variant (Variation ID: 636026). Based on the evidence outlined above, the variant was classified as a pathogenic, possibly hypomorphic founder allele in East Asian subpopulations. -

Retinal dystrophy

Pathogenic:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Uncertain

0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

.;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.60

T;T

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.11

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

H;H

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-7.9

D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.63

MVP

0.51

MPC

0.061

ClinPred

0.91

GERP RS

5.0

Varity_R

0.62

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over