rs752953889

Positions:

chr6-64066348-TA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001142800.2(EYS):c.6714delT(p.Ile2239fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000522 in 1,551,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

EYS
NM_001142800.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: -0.313

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-64066348-TA-T is Pathogenic according to our data. Variant chr6-64066348-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 357699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-64066348-TA-T is described in Lovd as [Pathogenic]. Variant chr6-64066348-TA-T is described in Lovd as [Pathogenic]. Variant chr6-64066348-TA-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYS	NM_001142800.2 linkuse as main transcript	c.6714delT	p.Ile2239fs	frameshift_variant	33/43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_001292009.2 linkuse as main transcript	c.6714delT	p.Ile2239fs	frameshift_variant	33/44		NP_001278938.1	Q5T1H1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EYS	ENST00000503581.6 linkuse as main transcript	c.6714delT	p.Ile2239fs	frameshift_variant	33/43	5	NM_001142800.2	ENSP00000424243.1	Q5T1H1-1
EYS	ENST00000370621.7 linkuse as main transcript	c.6714delT	p.Ile2239fs	frameshift_variant	33/44	1		ENSP00000359655.3	Q5T1H1-3
EYS	ENST00000398580.3 linkuse as main transcript	c.27delT	p.Ile10fs	frameshift_variant	1/10	5		ENSP00000381585.3	H0Y3Q4

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000381

AC:

AN:

157482

Hom.:

AF XY:

0.0000241

AC XY:

AN XY:

82906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000408

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000924

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000651

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000543

AC:

AN:

1398802

Hom.:

Cov.:

AF XY:

0.0000580

AC XY:

AN XY:

689780

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000282

Gnomad4 ASJ exome

AF:

0.0000795

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000640

Gnomad4 OTH exome

AF:

0.0000516

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000453

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Pathogenic:9

Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The EYS c.6714del 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, PM3_strong. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 23, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jun 03, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 23, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	May 13, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	EYS: PVS1, PM2, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change creates a premature translational stop signal (p.Ile2239Serfs*17) 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 (rs752953889, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 18976725, 21069908, 26667666, 29550188). This variant is also known as p.Pro2238ProfsX16. ClinVar contains an entry for this variant (Variation ID: 357699). 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	GeneDx	Mar 12, 2024	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: 32218477, 34426522, 31589614, 32037395, 31816670, 34906470, 37643323, 29550188, 25268133, 31964843, 36284460, 37322672, 36819107, 26667666, 25999674, 34662339, 25494902, 21069908, 33576794, 31074760, 34315337, 32531858, 32036094, 18976725) -

Retinitis pigmentosa

Pathogenic:4

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	The p.Ile2239SerfsTer17 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: PVS1, PM2, PP5. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 28, 2016	The EYS c.6714delT (p.Ile2239SerfsTer17) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Ile2239SerfsTer17 variant has been reported in a total of four individuals with autosomal recessive retinitis pigmentosa, including two homozygotes and two compound heterozygotes (Collin et al. 2008; Barragan et al. 2010; Katagiri et al. 2014; Ge et al. 2015). The variant was absent from the 1051 controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. The Ile2239 residue is highly conserved. Based on the evidence from the literature and due to the potential impact of frameshift variants, the p.Ile2239SerfsTer17 variant is classified as likely pathogenic for the autosomal recessive form of retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 13, 2022	Variant summary: EYS c.6714delT (p.Ile2239SerfsX17) 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. At least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.8e-05 in 157482 control chromosomes (gnomAD). c.6714delT has been reported in the literature as a biallelic genotype in multiple individuals affected with Retinitis Pigmentosa and has been shown to segregate with the disease phenotype in at least one family (e.g. Collin_2008, Barragan_2010, Weisschuh_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fourteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as either pathogenic (n= 13) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Retinal dystrophy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 30, 2019	- -
Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2023	- -

Autosomal recessive retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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