VCV000048558.15 - ClinVar

NM_206933.4(USH2A):c.6289_6302del (p.Leu2096_Ile2097insTer)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

7 out of 7 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_206933.4(USH2A):c.6289_6302del (p.Leu2096_Ile2097insTer)

Variation ID: 48558 Accession: VCV000048558.15

Type and length

Deletion, 14 bp

Location

Cytogenetic: 1q41 1: 216046454-216046467 (GRCh38) [ NCBI UCSC ] 1: 216219796-216219809 (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	Feb 24, 2015	Feb 25, 2025	May 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_206933.4:c.6289_6302del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_996816.3:p.Leu2096_Ile2097insTer
NC_000001.11:g.216046455_216046468del
NC_000001.10:g.216219797_216219810del
NG_009497.2:g.381982_381995del

Protein change

Other names

Canonical SPDI

NC_000001.11:216046453:CTGCCTGAATAGATC:C

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

ClinGen: CA262113 dbSNP: rs111033268 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.
USH2A		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	7392	8956

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.
Rare genetic deafness	Likely pathogenic (1)	criteria provided, single submitter	Aug 24, 2007	RCV000041884.5
Retinitis pigmentosa 39 Usher syndrome type 2A	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 9, 2024	RCV000673453.2
Retinitis pigmentosa 39	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 10, 2024	RCV003450873.3
not provided	Pathogenic (1)	criteria provided, single submitter	May 23, 2024	RCV001213783.7
Usher syndrome type 2A	Likely pathogenic (1)	criteria provided, single submitter	Nov 4, 2023	RCV003450872.1

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 (Jan 10, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004208340.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (Mar 16, 2018) C Contributing to aggregate classification	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Usher syndrome type 2A Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000798657.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (2) PubMed: 19788668‚ 20507924
Pathogenic (May 09, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Retinitis pigmentosa 39 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV005641049.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025
Pathogenic (May 23, 2024) C Contributing to aggregate classification	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: SCV001385433.6 First in ClinVar: Jul 16, 2020 Last updated: Feb 25, 2025	Publications: PubMed (5) PubMed: 10729113‚ 10909849‚ 20507924‚ 25649381‚ 19788668 Comment: This sequence change creates a premature translational stop signal (p.Ile2097) in the USH2A gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Ile2097) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs111033268, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of Usher syndrome 2A (USH2A) (PMID: 19788668, 20507924). ClinVar contains an entry for this variant (Variation ID: 48558). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Aug 24, 2007) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Rare genetic deafness Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000065580.6 First in ClinVar: May 03, 2013 Last updated: Feb 24, 2015	Number of individuals with the variant: 1
Likely pathogenic (Nov 04, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004181677.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Likely pathogenic (Nov 04, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004181678.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023

Comment:

This sequence change creates a premature translational stop signal (p.Ile2097*) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs111033268, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of Usher syndrome 2A (USH2A) (PMID: 19788668, 20507924). ClinVar contains an entry for this variant (Variation ID: 48558). 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
A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.	Lenassi E	European journal of human genetics : EJHG	2015	PMID: 25649381
Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa.	McGee TL	Journal of medical genetics	2010	PMID: 20507924
An audit of genetic testing in diagnosis of inherited retinal disorders: a prerequisite for gene-specific intervention.	Pradhan M	Clinical & experimental ophthalmology	2009	PMID: 19788668
Identification of novel USH2A mutations: implications for the structure of USH2A protein.	Dreyer B	European journal of human genetics : EJHG	2000	PMID: 10909849
Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type IIa.	Weston MD	American journal of human genetics	2000	PMID: 10729113

Text-mined citations for rs111033268 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 07, 2025

ClinVar Genomic variation as it relates to human health

NM_206933.4(USH2A):c.6289_6302del (p.Leu2096_Ile2097insTer)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs111033268 ...