NM_001142800.2:c.2528G>A

Variant names:

• chr6-64912597-C-T
• rs74419361
• NM_001142800.2:c.2528G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 10P and 6B. PM5 PP5_Very_Strong BP4 BS1_Supporting BS2

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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 U:2
• Conservation: PhyloP100: 6.15
• Publications: 18 publications found

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

ENSG00000308351 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-64912598-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1213994.
• PP5: Variant 6-64912597-C-T is Pathogenic according to our data. Variant chr6-64912597-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 636026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1148926). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 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 GnomAdExome4. There are 171 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142800.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	NM_001142800.2	MANE Select	c.2528G>A	p.Gly843Glu	missense	Exon 16 of 43	NP_001136272.1
	EYS	NM_001292009.2		c.2528G>A	p.Gly843Glu	missense	Exon 16 of 44	NP_001278938.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	ENST00000503581.6	TSL:5 MANE Select	c.2528G>A	p.Gly843Glu	missense	Exon 16 of 43	ENSP00000424243.1
	EYS	ENST00000370621.7	TSL:1	c.2528G>A	p.Gly843Glu	missense	Exon 16 of 44	ENSP00000359655.3
	ENSG00000308351	ENST00000833459.1		n.173-3726C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151954 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000256 AC: 4 AN: 156432 AF XY: 0.0000241

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 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.: 2 Cov.: 33 AF XY: 0.000248 AC XY: 171 AN XY: 690040

African (AFR) AF: 0.00 AC: 0 AN: 31586

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.0101 AC: 361 AN: 35718

South Asian (SAS) AF: 0.00 AC: 0 AN: 79220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078728

Other (OTH) AF: 0.0000345 AC: 2 AN: 57994

GnomAD4 genome AF: 0.000132 AC: 20 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41500

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00386 AC: 20 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000205 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 25 Pathogenic:6 Uncertain:1

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 04, 2025

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PM3 strong, PP1 strong, PP3 supporting

Feb 24, 2025

Revvity Omics, Revvity

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.

Jul 23, 2024

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 v4.0.0 dataset (total allele frequency: 0.025%). 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. 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)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000636026 /PMID: 29785639 /3billion dataset). 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.

Feb 11, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Sep 25, 2025

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, 36729443, 36819107, 34906470, 33691693, 34721897, 31253780, 31054281, 31814702, 33946315, 30718709, 33247286, 32218477, 22363543, 32079136, 36284460, 35109811, 33514863)

Retinitis pigmentosa Pathogenic:1 Uncertain:1

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.

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.11	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		6.1
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.63
MVP		0.51
MPC		0.061
ClinPred		0.91	D
GERP RS		5.0
Varity_R		0.62
gMVP		0.99
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs74419361; hg19: chr6-65622490;