VCV002675292.2 - ClinVar

NM_001142800.2(EYS):c.9337_9350del (p.Lys3113fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001142800.2(EYS):c.9337_9350del (p.Lys3113fs)

Variation ID: 2675292 Accession: VCV002675292.2

Type and length

Deletion, 14 bp

Location

Cytogenetic: 6q12 6: 63720681-63720694 (GRCh38) [ NCBI UCSC ] 6: 64430577-64430590 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 30, 2023	Feb 20, 2024	Oct 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001142800.2:c.9337_9350del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001136272.1:p.Lys3113fs	frameshift
NM_001370348.2:c.6976_6989del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_001290259.2:c.6976_6989del		3 prime UTR
NM_001292009.2:c.9400_9413del	NP_001278938.1:p.Lys3134fs	frameshift
NM_001370349.2:c.6976_6989del		3 prime UTR
NM_001370350.2:c.6976_6989del		3 prime UTR
NM_015153.4:c.6976_6989del		3 prime UTR
NC_000006.12:g.63720684_63720697del
NC_000006.11:g.64430580_64430593del
NG_023443.2:g.1991532_1991545del
NG_034034.2:g.89884_89897del

... more HGVS ... less HGVS

Protein change

K3113fs, K3134fs

Other names

Canonical SPDI

NC_000006.12:63720680:AATACAACATCTTTAAT:AAT

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PHF3		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	149	703
EYS		-	-	GRCh38 GRCh37	4233	4794

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Retinitis pigmentosa 25	Pathogenic (1)	criteria provided, single submitter	Mar 23, 2023	RCV003468040.1
not provided	Pathogenic (1)	criteria provided, single submitter	Oct 22, 2023	RCV003661059.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 25 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004193512.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Oct 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004372782.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (6) PubMed: 33576794‚ 36819107‚ 18976725‚ 29159838‚ 30337596‚ 31074760 Comment: This sequence change creates a premature translational stop signal (p.Lys3113Phefs8) in the EYS gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Lys3113Phefs8) in the EYS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the EYS protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with retinitis pigmentosa (PMID: 33576794, 36819107). This variant disrupts a region of the EYS protein in which other variant(s) (p.Tyr3135*) have been determined to be pathogenic (PMID: 18976725, 29159838, 30337596, 31074760). 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. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Lys3113Phefs*8) in the EYS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the EYS protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with retinitis pigmentosa (PMID: 33576794, 36819107). This variant disrupts a region of the EYS protein in which other variant(s) (p.Tyr3135*) have been determined to be pathogenic (PMID: 18976725, 29159838, 30337596, 31074760). 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis.	Panneman DM	Frontiers in cell and developmental biology	2023	PMID: 36819107
Molecular Epidemiology in 591 Italian Probands With Nonsyndromic Retinitis Pigmentosa and Usher Syndrome.	Colombo L	Investigative ophthalmology & visual science	2021	PMID: 33576794
Extending the Spectrum of EYS-Associated Retinal Disease to Macular Dystrophy.	Pierrache LHM	Investigative ophthalmology & visual science	2019	PMID: 31074760
A new approach based on targeted pooled DNA sequencing identifies novel mutations in patients with Inherited Retinal Dystrophies.	Ezquerra-Inchausti M	Scientific reports	2018	PMID: 30337596
EYS mutation update: In silico assessment of 271 reported and 26 novel variants in patients with retinitis pigmentosa.	Messchaert M	Human mutation	2018	PMID: 29159838
Identification of a 2 Mb human ortholog of Drosophila eyes shut/spacemaker that is mutated in patients with retinitis pigmentosa.	Collin RW	American journal of human genetics	2008	PMID: 18976725

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001142800.2(EYS):c.9337_9350del (p.Lys3113fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...