rs749909863

chr6-64230600-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001142800.2(EYS):c.6416G>A(p.Cys2139Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000538 in 1,543,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C2139R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 U:1
• Conservation: PhyloP100: 1.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain EGF-like 21 (size 41) in uniprot entity EYS_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_001142800.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-64230601-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1066550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874
• PP5: Variant 6-64230600-C-T is Pathogenic according to our data. Variant chr6-64230600-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-64230600-C-T is described in Lovd as [Likely_pathogenic]. Variant chr6-64230600-C-T is described in Lovd as [Pathogenic]. Variant chr6-64230600-C-T is described in Lovd as [Likely_pathogenic]. Variant chr6-64230600-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.6416G>A	p.Cys2139Tyr	missense_variant	31/43	ENST00000503581.6
EYS	NM_001292009.2	c.6416G>A	p.Cys2139Tyr	missense_variant	31/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.6416G>A	p.Cys2139Tyr	missense_variant	31/43	5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.6416G>A	p.Cys2139Tyr	missense_variant	31/44	1		P2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000144 AC: 22 AN: 152386 Hom.: 0 AF XY: 0.0000990 AC XY: 8 AN XY: 80844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00166

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000684

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000518 AC: 72 AN: 1391284 Hom.: 0 Cov.: 30 AF XY: 0.0000526 AC XY: 36 AN XY: 684740

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000619

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.0000410

Gnomad4 OTH exome AF: 0.0000695

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000453 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 25 Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 14, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.41). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000189230). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 20237254) and to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:20237254). A different missense change at the same codon (p.Cys2139Arg) has been reported to be associated with EYS related disorder (ClinVar ID: VCV001066550 / PMID: 25366773). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 26, 2023	- -
Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The EYS c.6416G>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: PS1, PM2, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 2139 of the EYS protein (p.Cys2139Tyr). This variant is present in population databases (rs749909863, gnomAD 0.2%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 20333770, 25356976, 25753737). 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: 189230). Advanced 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 at Invitae 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2016	- -

Retinal dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 19, 2018	- -
Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

EYS-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 28, 2023

The EYS c.6416G>A variant is predicted to result in the amino acid substitution p.Cys2139Tyr. This variant, in either the compound heterozygous or homozygous states, has been reported in patients with inherited retinal disorders (Supplemental Table S5, Huang et al. 2015. PubMed ID: 25356976; Chen et al. 2015. PubMed ID: 25753737; Audo et al. 2010. PubMed ID: 20333770). This variant is reported in 0.18% of alleles in individuals of East Asian descent in gnomAD. Taken together, this variant is interpreted as pathogenic. -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Apr 01, 2021

The p.Cys2139Tyr variant in EYS was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

not specified Uncertain:1

Uncertain significance, flagged submission

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 15, 2014

The Cys2139Tyr variant in EYS has been reported in 3 compound heterozygous and 1 heterozygous individuals with retinitis pigmentosa and was found to segregate with disease in 3 compound heterozygous family members (Audo 2010, Abd El-Aziz 2010, Jin 2014). This variant was not identified in large population studies. Computational analyses (biochemical amino acid properties, conservation, PolyPhen2, and SIFT) don't provide strong support for or against and impact to the protein and one mammal carries a tyrosine (Tyr) at this position. In summary, while segregation studies and the presence of this variant in combination with other reported pathogenic variants indicate this variant may be disease-causing, the presence of the variant amino acid in a mammal raises some concern and additional studies are required to fully establish its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.76	T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	4.2	H;H
MutationTaster	Benign	0.95	N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;D
Vest4		0.68
MutPred		0.99		Gain of ubiquitination at K2141 (P = 0.1215);Gain of ubiquitination at K2141 (P = 0.1215);
MVP		0.49
MPC		0.056
ClinPred		0.79	D
GERP RS		3.1
Varity_R		0.97
gMVP		0.79

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

LitVar

Other links and lift over

dbSNP: rs749909863; hg19: chr6-64940493;