rs199740930

Positions:

• chr6-65057613-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_001142800.2(EYS):​c.2137+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000358 in 1,531,944 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (4 hom.)
• Consequence: EYS NM_001142800.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19 U:1
• Conservation: PhyloP100: 4.27

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 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.011976683 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6, offset of -36, new splice context is: ctgGTaatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 6-65057613-C-T is Pathogenic according to our data. Variant chr6-65057613-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-65057613-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYS	NM_001142800.2	c.2137+1G>A		splice_donor_variant, intron_variant		ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.2137+1G>A		splice_donor_variant, intron_variant			NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.2137+1G>A		splice_donor_variant, intron_variant		5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7	c.2137+1G>A		splice_donor_variant, intron_variant		1		ENSP00000359655.3

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000743 AC: 116 AN: 156184 Hom.: 1 AF XY: 0.000689 AC XY: 57 AN XY: 82776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000243

Gnomad ASJ exome AF: 0.00883

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000527

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000332

Gnomad OTH exome AF: 0.000686

GnomAD4 exome AF: 0.000358 AC: 494 AN: 1379816 Hom.: 4 Cov.: 28 AF XY: 0.000362 AC XY: 247 AN XY: 681964

Gnomad4 AFR exome AF: 0.0000642

Gnomad4 AMR exome AF: 0.000196

Gnomad4 ASJ exome AF: 0.00742

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000431

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.000820

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.000417 AC XY: 31 AN XY: 74366

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000754 Hom.: 1

Bravo AF: 0.000359

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000943 AC: 3

ExAC AF: 0.00102 AC: 25

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 25 Pathogenic:9 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Jun 29, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 25 (MIM#602772). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 123 heterozygotes, 1 homozygote). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple retinitis pigmentosa individuals, including homozygotes, and is classified as likely pathogenic/pathogenic by diagnostic laboratories in ClinVar (PMIDs: 28704921, 32728228). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, flagged submission	clinical testing	Blueprint Genetics	Aug 01, 2019	We have identified this variant in >10 individuals with a retinal dystrophy clinical indication. The variant was only seen in the heterozygous state in these individuals. Further, nearly half had a LP/P variant in another gene which explained their phenotype. -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NG_023443.2(NM_001142800.1):c.2137+1G>A in the EYS gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This sequence change affects a donor splice site in intron 13 of the EYS gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been observed as homozygous in an individual affected with retinitis pigmentosa (PMID: 28704921). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3_Supporting; PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 11, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 02, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Oct 11, 2020	- -

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change affects a donor splice site in intron 13 of the EYS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is present in population databases (rs199740930, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. Disruption of this splice site has been observed in individual(s) with retinitis pigmentosa (PMID: 28704921, 30718709, 33576794). ClinVar contains an entry for this variant (Variation ID: 421249). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2024	Observed with a second EYS variant, phase unknown, in patients with retinitis pigmentosa in literature; however, these patients had variants in other genes that may have also contributed to the phenotype (PMID: 32728228, 33576794, 30718709); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30718709, 28704921, 34426522, 31589614, 31456290, 31980526, 32552793, 33576794, 32728228, 37734845, 36941944, 37644014, 31964843, 35272565, Abiib[thesis]2023, 37028505, 38465142) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2019	- -

Retinitis pigmentosa Pathogenic:4

Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2022	Variant summary: EYS c.2137+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 0.00074 in 156184 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.00074 vs 0.0034). The variant, c.2137+1G>A, has been reported in the literature in the homozygous and compound heterozygous state in individuals affected with Retinitis Pigmentosa (example McGuigan_2017, Jespersgaard_2019, Sharon_2020, Colombo_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. There have been 13 assessments for this variant submitted to ClinVar after 2014. Five classified the variant as pathogenic, seven as likely pathogenic, and one as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -

EYS-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 28, 2024

The EYS c.2137+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the homozygous state or with a second potentially causative variant in several individuals with suspected retinitis pigmentosa (McGuigan et al. 2017. PubMed ID: 28704921; Cundy et al. 2020. PubMed ID: 32728228; Colombo et al. 2021. PubMed ID: 33576794). This variant is reported in 0.89% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygous individual. Variants that disrupt the consensus splice donor site in EYS are expected to be pathogenic. In ClinVar, this variant has been interpreted as likely pathogenic or pathogenic by outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/421249/). We classify this variant as likely pathogenic. -

Retinal dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.97	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.57		Position offset: 37
DS_DL_spliceai		0.97		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199740930; hg19: chr6-65767506;