dbSNP rs794727120: EYS:p.Gln732* (chr6-64997647-G-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

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

The NM_001142800.2(EYS):c.2194C>T(p.Gln732*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000858 in 1,398,880 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

EYS
NM_001142800.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.76

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 6-64997647-G-A is Pathogenic according to our data. Variant chr6-64997647-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 194358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-64997647-G-A is described in Lovd as [Pathogenic]. Variant chr6-64997647-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.2194C>T	p.Gln732*	stop_gained	Exon 14 of 43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_001292009.2 link	c.2194C>T	p.Gln732*	stop_gained	Exon 14 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.2194C>T	p.Gln732*	stop_gained	Exon 14 of 43	5	NM_001142800.2	ENSP00000424243.1		Q5T1H1-1
EYS	ENST00000370621.7 link	c.2194C>T	p.Gln732*	stop_gained	Exon 14 of 44	1		ENSP00000359655.3		Q5T1H1-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000858

AC:

AN:

1398880

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

689972

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000111

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Pathogenic:3

May 10, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Jan 20, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln732*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 23591405). ClinVar contains an entry for this variant (Variation ID: 194358). For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy

Pathogenic:1

Aug 28, 2017

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Pathogenic:1

Apr 01, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Gln732Ter 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.077

FATHMM_MKL

Uncertain

0.86

Vest4

0.93

GERP RS

0.27

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

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