chr6-63721375-TTCTGCATG-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001142800.2(EYS):c.8648_8655delCATGCAGA(p.Thr2883LysfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.000365 in 1,551,816 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00064 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 1 hom. )

Consequence

EYS
NM_001142800.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 6.86

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:

PHF3 (HGNC:8921): (PHD finger protein 3) This gene encodes a member of a PHD finger-containing gene family. This gene may function as a transcription factor and may be involved in glioblastomas development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

PHF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 38 pathogenic variants in the truncated region.

PP5

Variant 6-63721375-TTCTGCATG-T is Pathogenic according to our data. Variant chr6-63721375-TTCTGCATG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-63721375-TTCTGCATG-T is described in Lovd as [Pathogenic]. Variant chr6-63721375-TTCTGCATG-T is described in Lovd as [Likely_pathogenic]. Variant chr6-63721375-TTCTGCATG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.8648_8655delCATGCAGA	p.Thr2883LysfsTer4	frameshift_variant	Exon 43 of 43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
PHF3	NM_001370348.2 link	c.7669_7676delCTGCATGT		3_prime_UTR_variant	Exon 16 of 16	ENST00000262043.8	NP_001357277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EYS	ENST00000503581.6 link	c.8648_8655delCATGCAGA	p.Thr2883LysfsTer4	frameshift_variant	Exon 43 of 43	5	NM_001142800.2	ENSP00000424243.1	Q5T1H1-1
EYS	ENST00000370621.7 link	c.8711_8718delCATGCAGA	p.Thr2904LysfsTer4	frameshift_variant	Exon 44 of 44	1		ENSP00000359655.3	Q5T1H1-3
PHF3	ENST00000262043.8 link	c.7669_7676delCTGCATGT		3_prime_UTR_variant	Exon 16 of 16	5	NM_001370348.2	ENSP00000262043.4	Q92576-1
PHF3	ENST00000505138.1 link	c.361+10015_361+10022delCTGCATGT		intron_variant	Intron 3 of 4	3		ENSP00000421417.1	H0Y8L0

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152126

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:

0.00782

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000750

AC:

118

AN:

157422

Hom.:

AF XY:

0.000698

AC XY:

AN XY:

83080

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00645

Gnomad NFE exome

AF:

0.000131

Gnomad OTH exome

AF:

0.000225

GnomAD4 exome

AF:

0.000335

AC:

469

AN:

1399572

Hom.:

AF XY:

0.000343

AC XY:

237

AN XY:

690282

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:

0.00636

Gnomad4 NFE exome

AF:

0.000125

Gnomad4 OTH exome

AF:

0.000344

GnomAD4 genome

AF:

0.000644

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74452

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:

0.00782

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000119

Hom.:

Bravo

AF:

0.0000869

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Pathogenic:8

Mar 06, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 23, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 22, 2023

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: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The EYS c.8648_8655del 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. Based on this evidence we have classified this variant as Pathogenic. -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NM_001142800.1:c.8648_8655delCATGCAGA in the EYS gene has an allele frequency of 0.006 in European (Finnish) subpopulation in the gnomAD database. This sequence change results in a premature translational stop signal in the EYS gene (p.Thr2883Lysfs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 262 amino acids of the EYS protein. This variant has been observed in a patient with retinitis pigmentosa, in a compound heterozygous state with c.4350_4356del7 (p.K1450KfsX3) (PMID: 20537394). This variant is also known as c.8710_8717del8 (p.T2904KfsX4) in the literature. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3; PP4. -

Feb 02, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 29, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Jul 30, 2024

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.Thr2883Lysfs*4) in the EYS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 262 amino acid(s) of the EYS protein. This variant is present in population databases (rs528919874, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 20537394). It has also been observed to segregate with disease in related individuals. This variant is also known as c.8710_8717del8 (p.T2904KfsX4). ClinVar contains an entry for this variant (Variation ID: 550019). This variant disrupts a region of the EYS protein in which other variant(s) (p.Tyr2935*) have been determined to be pathogenic (PMID: 22363543). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Oct 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Commonly seen in cis with the p.(C385*) variant in individuals of Finish background (Avela et al., 2018); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 262 amino acids are lost and replaced with 3 incorrect amino acids; This variant is associated with the following publications: (PMID: 30718709, 20537394, 29159838, 28704921, 29550188, 31429209, 32531858, 29068140, 33833316) -

Retinal dystrophy

Pathogenic:2

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 09, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Pathogenic:2

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 24, 2023

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.8648_8655delCATGCAGA (p.Thr2883LysfsX4) is located in the last exon, and results in a premature termination codon that is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing a part of the 3144 amino acids long protein. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00075 in 157422 control chromosomes, predominantly at a frequency of 0.0064 within the Finnish subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency in the Finnish subpopulation is higher than the estimated maximal expected allele frequency for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.0034). However, the Finnish subpopulation has been recently reported to be enriched for certain founder mutations in EYS (Avela_2018, Avela_2019). The presence of homozygotes in controls suggests that this variant may have incomplete penetrance and/or is associated with a later onset of disease. The variant, c.8648_8655delCATGCAGA, has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Retinitis Pigmentosa (e.g. Littink_2010, Westin_2021), and was also reported in cis with the c.1155T>A (p.Cys385X) variant in multiple Finish patients (Avela_2018, Avela_2019). 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. Nine ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic (n = 7) or likely pathogenic (n = 2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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