VCV000002351.96 - ClinVar

NM_206933.4(USH2A):c.2299del (p.Glu767fs)

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.

(53)

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

This variant is part of a Haplotype

NM_206933.2(USH2A):c.[2299del;4714C>T]

Identifiers

NM_206933.4(USH2A):c.2299del (p.Glu767fs)

Variation ID: 2351 Accession: VCV000002351.96

Type and length

Deletion, 1 bp

Location

Cytogenetic: 1q41 1: 216247095 (GRCh38) [ NCBI UCSC ] 1: 216420437 (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	May 3, 2013	Oct 20, 2024	Oct 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_206933.4:c.2299del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_996816.3:p.Glu767fs	frameshift
NM_206933.4:c.2299delG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_007123.5:c.2299delG
NM_007123.6:c.2299del	NP_009054.6:p.Glu767fs	frameshift
NM_206933.3:c.2299del
NM_206933.3:c.2299delG
NC_000001.11:g.216247095del
NC_000001.10:g.216420437del
NG_009497.2:g.181354del
NG_076570.1:g.469del

... more HGVS ... less HGVS

Protein change

E767fs

Other names

p.Glu767SerfsX21
NP_996816.3:p.(Glu767SerfsTer21)

Canonical SPDI

NC_000001.11:216247094: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.

The Genome Aggregation Database (gnomAD) 0.00055

Trans-Omics for Precision Medicine (TOPMed) 0.00071

The Genome Aggregation Database (gnomAD), exomes 0.00076

Exome Aggregation Consortium (ExAC) 0.00079

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00096

Links

ClinGen: CA252226 OMIM: 608400.0001 dbSNP: rs80338903 VarSome

Comment on variant

NCBI staff reviewed the sequence information reported in PubMed 9624053 Fig. 2B to determine the location of this allele on the current reference sequence.

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		-	-	GRCh38 GRCh37	7071	8566

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.
Usher syndrome type 2A	Pathogenic (13)	criteria provided, multiple submitters, no conflicts	Oct 1, 2024	RCV000002445.30
Retinitis pigmentosa	Pathogenic (4)	criteria provided, single submitter	Apr 1, 2021	RCV000032524.10
Retinal dystrophy	Pathogenic (2)	criteria provided, single submitter	Aug 15, 2019	RCV000210326.7
not provided	Pathogenic (11)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000254870.50
Usher syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 24, 2023	RCV000504641.6
Abnormal autonomic nervous system physiology Abnormal upper limb bone morphology Abnormality of the upper limb Abnormality of upper limb joint Anxiety Brisk reflexes Chronic pain Cognitive impairment Dislocated radial head Distal arthrogryposis High palate Multiple joint contractures Short stature	Pathogenic (1)	criteria provided, single submitter	-	RCV000735362.5
Macular dystrophy	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787895.3
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Mar 3, 2020	RCV000623326.8
Cone-rod dystrophy	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787897.3
Congenital stationary night blindness	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787899.3
Rare genetic deafness Usher syndrome	Pathogenic (1)	criteria provided, single submitter	Sep 30, 2014	RCV000824793.7
Retinitis pigmentosa 39	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Mar 30, 2024	RCV000191141.15
Retinitis pigmentosa 39 Usher syndrome type 2A	Pathogenic (1)	criteria provided, single submitter	Mar 30, 2022	RCV002504737.4
not specified	Pathogenic (1)	criteria provided, single submitter	Jul 31, 2018	RCV001000453.11
USH2A-related disorder	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 5, 2022	RCV001095692.10
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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 (Oct 14, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000225952.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (4) PubMed: 24160897‚ 24607488‚ 25649381‚ 9624053 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A http://www.lovd.nl/USH2A http://www.lovd.nl/USH2A Number of individuals with the variant: 11 Sex: mixed
Pathogenic (Sep 30, 2014)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Rare genetic deafness Usher syndrome Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000065508.6 First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019	Publications: PubMed (6) PubMed: 12112664‚ 15025721‚ 14970843‚ 11402400‚ 10909849‚ 10729113 Comment: The p.Glu767fs variant in USH2A is a common pathogenic variant known to be assoc iated with Usher syndrome (Weston 2000, Dreyer 2000, Dreyer 2001, Najera … (more) The p.Glu767fs variant in USH2A is a common pathogenic variant known to be assoc iated with Usher syndrome (Weston 2000, Dreyer 2000, Dreyer 2001, Najera 2002, O uyang 2004, Aller 2004). (less) Number of individuals with the variant: 64
Pathogenic (Jul 31, 2018)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001157289.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020	Comment: The Glu767fs variant (rs80338903) has been observed in multiple cohorts of patients with Usher Syndrome, Type II (selected references: Eudy 1998, Dreyer 2001, Aller 2010). … (more) The Glu767fs variant (rs80338903) has been observed in multiple cohorts of patients with Usher Syndrome, Type II (selected references: Eudy 1998, Dreyer 2001, Aller 2010). It is one of the most common pathogenic alleles of USH2A, and it is estimated that this variant accounts for 16% (Weston 2000) to 76% (Ouyang 2004) of all pathogenic USH2A variant. This variant is listed in the Genome Aggregation Database (gnomAD) database with a frequency in Latino populations of 0.20% (identified in 34 out of 34,442 chromosomes). (less)
Pathogenic (Feb 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Affected status: yes Allele origin: germline	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals Accession: SCV001156376.1 First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020	Number of individuals with the variant: 1 Clinical Features: Congenital sensorineural hearing impairment (present) , Retinal dystrophy (present) , Posterior subcapsular cataract (present)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001162881.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020
Pathogenic (Aug 15, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239242.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Oct 25, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Usher syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001362171.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (3) PubMed: 14970843‚ 29953849‚ 24607488 Comment: Variant summary: USH2A c.2299delG (p.Glu767SerfsX21) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: USH2A c.2299delG (p.Glu767SerfsX21) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00076 in 250832 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher syndrome (0.00076 vs 0.013), allowing no conclusion about variant significance. c.2299delG has been reported in the literature in multiple individuals affected with Usher syndrome. This variant appears to be a common USH2A mutation contributing to Usher Syndrome Type II (e.g. Aller_2004, Calzetti_2018 and Gene Reviews). Lenassi et al suggest that this change could disrupt an exonic splicing enhancer and create an exonic splicing silencer within exon 13 and therefore affect splicing of exons 12 and 13 of USH2A (Lenassi_2014). Nine ClinVar submitters (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Dec 17, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Usher syndrome type 2A Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194141.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (2) PubMed: 10909849‚ 24607488 Comment: NM_206933.2(USH2A):c.2299delG(aka E767Sfs21) is classified as pathogenic in the context of USH2A-related disorders. Sources cited for classification include the following: PMID 10909849 and 24607488. Classification of … (more) NM_206933.2(USH2A):c.2299delG(aka E767Sfs21) is classified as pathogenic in the context of USH2A-related disorders. Sources cited for classification include the following: PMID 10909849 and 24607488. Classification of NM_206933.2(USH2A):c.2299delG(aka E767Sfs*21)is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446853.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Rod-cone dystrophy (present) Sex: female
Pathogenic (Sep 26, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001448876.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1 Sex: male
Pathogenic (Apr 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761479.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022	Publications: PubMed (4) PubMed: 9624053‚ 20301515‚ 22135276‚ 24607488 Comment: The USH2A c.2299del variant is classified as PATHOGENIC (PVS1, PS4, PM3) This USH2A c.2299del variant is located in exon 13/72 and is predicted to cause … (more) The USH2A c.2299del variant is classified as PATHOGENIC (PVS1, PS4, PM3) This USH2A c.2299del variant is located in exon 13/72 and is predicted to cause a shift in the reading frame at codon 767 (PVS1). This recurrent variant has been reported as the most common USH2A pathogenic variant (PMID: 20301515, PMID:9624053, PMID:22135276, PMID:24607488) (PS4). This variant has been detected in trans with another pathogenic variant for this recessive condition in both this individual and in other reported cases in the literature (PM3) and has also been reported as pathogenic in a homozygous state. This variant is in dbSNP (rs80338903) and has been reported as pathogenic for Usher syndrome and Retinitis pigmentosa by other diagnostic laboratories in ClinVar (ClinVar Variation ID: 2351) and in the disease database HGMD (CD982997). (less)
Pathogenic (Mar 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002805172.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Nov 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004182442.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Nov 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004182441.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Nov 24, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020836.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Baylor Genetics Study: Adult_WES Accession: SCV000245550.2 First in ClinVar: Sep 29, 2015 Last updated: Jun 17, 2024	Publications: PubMed (1) PubMed: 26633545
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormality of the upper limb Abnormal upper limb bone morphology Abnormality of upper limb joint Anxiety Brisk reflexes Chronic pain Cognitive impairment Dislocated radial head Distal arthrogryposis Abnormal autonomic nervous system physiology High palate Multiple joint contractures Short stature Affected status: yes Allele origin: germline	Center for Personalized Medicine, Children's Hospital Los Angeles Accession: SCV000854516.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Sex: female
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	USH2A-Related Disorders Affected status: yes Allele origin: inherited	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill Study: NSIGHT-NC NEXUS Accession: SCV001251499.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (4) PubMed: 20301515‚ 18641288‚ 11402400‚ 15326663 Comment: The c.2299delG (p.E767Sfs) variant is one of the most common pathogenic variants in USH2A and has been previously reported in multiple individuals with Usher syndrome … (more) The c.2299delG (p.E767Sfs) variant is one of the most common pathogenic variants in USH2A and has been previously reported in multiple individuals with Usher syndrome type IIA or nonsyndromic retinitis pigmentosa (PMID: 18641288; 11402400; 15326663). (less) Number of individuals with the variant: 1
Pathogenic (Apr 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinitis pigmentosa 39 Affected status: yes Allele origin: germline	Ocular Genomics Institute, Massachusetts Eye and Ear Accession: SCV001573518.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (9) PubMed: 28041643‚ 20301515‚ 25649381‚ 25404053‚ 25097241‚ 24944099‚ 24607488‚ 20145675‚ 12525556 Comment: The USH2A c.2299del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more) The USH2A c.2299del 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, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACGS Guidelines, 2016) Method: clinical testing	Retinitis pigmentosa 39 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760022.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021
Pathogenic (-)	criteria provided, single submitter (ACGS Guidelines, 2016) Method: clinical testing	Usher syndrome type 2A Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760021.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021
Pathogenic (Jun 28, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Affected status: yes Allele origin: germline	DBGen Ocular Genomics Accession: SCV001816033.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Number of individuals with the variant: 2 Sex: female Ethnicity/Population group: unspecified Geographic origin: Argentina
Pathogenic (Jan 13, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321994.7 First in ClinVar: Oct 09, 2016 Last updated: Apr 17, 2019	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22581970, 9624053, 32141364, 27344577, 20145675, 29847639, 23352160, 18665195, 26872967, 12525556, 11402400, 24607488, 29151245, 25097241, 15325563, 14970843, 26969326, 24160897, 25404053, 27460420, 22135276, 23924366, 17296898, 25649381, 24944099, 22495311, 21234346, 21174530, 11311042, 10775529, 10729113, 26633545, 10909849, 23891399, 20301515, 15025721, 12112664, 19881469, 17405132, 10090909, 30337596, 28157192, 28838317, 29953849, 31231422, 31266775, 32581362, 31827275, 31980526, 32176120, 32036094, 32664777, 31589614, 33576794, 30755392, 32853555) (less)
Pathogenic (Apr 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Retinitis pigmentosa (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001950408.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Publications: PubMed (10) PubMed: 34906470‚ 28041643‚ 20301515‚ 25649381‚ 25404053‚ 25097241‚ 24944099‚ 24607488‚ 20145675‚ 12525556 Comment: The p.Glu767SerfsTer21 variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more) The p.Glu767SerfsTer21 variant in USH2A 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, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
Pathogenic (Jan 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	USH2A-related disorder Affected status: yes Allele origin: germline	DASA Accession: SCV002061238.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022	Publications: PubMed (8) PubMed: 20301515‚ 31836858‚ 30718709‚ 29953849‚ 25649381‚ 25404053‚ 23924366‚ 12525556 Comment: The c.2299del;p.(Glu767Serfs21) is a null frameshift variant (NMD) in the USH2A gene and predicts alteration of the nonsense-mediate decay - NMD is present in a … (more) The c.2299del;p.(Glu767Serfs21) is a null frameshift variant (NMD) in the USH2A gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 2351; PMID: 20301515; 31836858; 30718709; 29953849;25649381; 25404053; 23924366; 12525556) - PS4. The variant is present at low allele frequencies population databases (rs80338903– gnomAD 0.04996%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Glu767Serfs*21) was detected in trans with a pathogenic variant (PMID: 31836858; 30718709; 29953849;25649381; 25404053; 23924366; 12525556) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 23924366; 12525556) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 1 Sex: male Geographic origin: Brazil
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: yes Allele origin: germline	3billion Accession: SCV002521582.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.070%). Frameshift: predicted to result in a loss … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.070%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002351). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Retinal dystrophy (present)
Pathogenic (Jan 11, 2023)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Usher syndrome type 2A Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV004014655.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (7) PubMed: 36011334‚ 20301515‚ 26629787‚ 25649381‚ 29953849‚ 9624053‚ 24607488 Comment: The USH2A c.2299del (p.Glu767SerfsTer21) variant results in the deletion of a nucleotide at position c.2299, causing a shift in the protein reading frame that is … (more) The USH2A c.2299del (p.Glu767SerfsTer21) variant results in the deletion of a nucleotide at position c.2299, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is predicted, though RNA expression studies performed on nasal epithelial cells suggest that the c.2299del variant could alternately disrupt splicing, leading to skipping of exon 13 or exons 12 and 13 (PMID: 24607488). The c.2299del variant is the most common disease-causing variant in the USH2A gene, and is estimated to account for over 20% of disease-causing alleles among individuals with Usher syndrome type 2, but has also been reported in individuals with non-syndromic retinitis pigmentosa (PMID: 9624053; PMID: 20301515, GeneReviews NBK1341; PMID: 25649381; PMID: 29953849; PMID: 36011334). The highest frequency of this allele in the Genome Aggregation Database is 0.001778 in the Latino/Admixed American population (version 2.1.1). Based on the available evidence, the c.2299del (p.Glu767SerfsTer21) variant is classified as pathogenic for Usher syndrome type 2. (less)
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Usher syndrome Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030341.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 Comment: This variant was classified as Pathogenic based on ACMG criteria: PVS1, PS4, PM2, PP5.	Publications: PubMed (1) PubMed: 36909829 Comment: Clinical significance based on ACMG v2.0 Number of individuals with the variant: 1 Sex: male Geographic origin: Portugal
Pathogenic (Jan 30, 2024)	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: SCV000940875.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (10) PubMed: 10729113‚ 10909849‚ 20507924‚ 25649381‚ 9624053‚ 11402400‚ 14970843‚ 15325563‚ 25097241‚ 25404053 Comment: This sequence change creates a premature translational stop signal (p.Glu767Serfs21) 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.Glu767Serfs21) 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 (rs80338903, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with non-syndromic autosomal recessive retinitis pigmentosa and is a common Usher syndrome type II allele (PMID: 9624053, 11402400, 14970843, 15325563, 25097241, 25404053). This variant is also known as 2314delG. ClinVar contains an entry for this variant (Variation ID: 2351). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 03, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000740743.5 First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 15025721‚ 17405132 Comment: The alteration results in a premature stop codon: _x000D_ _x000D_ The c.2299delG (p.E767Sfs21) alteration, located in exon 13 (coding exon 12) of the USH2A gene, … (more) The alteration results in a premature stop codon: _x000D_ _x000D_ The c.2299delG (p.E767Sfs21) alteration, located in exon 13 (coding exon 12) of the USH2A gene, consists of a deletion of one nucleotide at position 2299, causing a translational frameshift with a predicted alternate stop codon after 21 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration has been observed in affected individuals:_x000D_ _x000D_ The c.2299delG alteration is the most common alteration found in Usher syndrome type II (Ouyang, 2004; Baux, 2007). Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV001244816.3 First in ClinVar: May 04, 2020 Last updated: Jul 23, 2024	Publications: PubMed (1) PubMed: 29953849 Comment: 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 … (more) 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 Usher syndrome, type 2A (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (198 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported in patients with both retinitis pigmentosa and Usher syndrome (Decipher, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is one of the most common disease causing variants in the USH2A gene, and has been reported in patients with both Usher syndrome and retinitis pigmentosa (ClinVar, PMID: 29953849). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Jun 10, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV005200866.1 First in ClinVar: Sep 08, 2024 Last updated: Sep 08, 2024	Comment: PVS1, PS3, PM3_Very Strong, PM6
Pathogenic (Oct 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004032322.3 First in ClinVar: Sep 09, 2023 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1, PM3_VSTR, PP1_MOD Clinical Features: Retinitis pigmentosa (present) , Visual impairment (present) , Progressive visual loss (present) , Progressive hearing impairment (present) , Hearing impairment (present) Sex: male
Pathogenic (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248858.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: USH2A: PM3:Very Strong, PVS1, PP1:Strong, PM2 Number of individuals with the variant: 19
Pathogenic (Dec 01, 2009)	no assertion criteria provided Method: literature only	USHER SYNDROME, TYPE IIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022603.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 27, 2015	Publications: PubMed (7) PubMed: 9624053‚ 10090909‚ 10729113‚ 11402400‚ 15025721‚ 17405132‚ 19881469 Comment on evidence: By heteroduplex analysis, Eudy et al. (1998) identified a 2299delG mutation (originally reported by them as 2314delG) in the USH2A gene in 21 of 96 … (more) By heteroduplex analysis, Eudy et al. (1998) identified a 2299delG mutation (originally reported by them as 2314delG) in the USH2A gene in 21 of 96 probands with Usher syndrome type IIa (USH2A; 276901); 8 of them were homozygous and 13 heterozygous. All but 2 were of northern European ancestry (Swedish, Dutch, German, or English). The 2 non-northern European patients were both homozygous for the 2299G deletion; one was from Spain and the other was an African American from Nebraska, U.S. Examination of various haplotypes failed to reveal any substantial disequilibrium with the 2299delG mutation, suggesting that the mutation did not arise in a common ancestor. The 2299delG mutation caused a frameshift at codon 772, after which the open reading frame continued for 20 codons and ended as TAG. Liu et al. (1999) performed a mutation analysis of the USH2A gene in 23 families with Usher syndrome, 10 of which had a diagnosis of atypical Usher syndrome, from the United Kingdom and China. They found that most of the families with USH2 carried the 2299delG mutation. Of 12 families with the 2299delG mutation, 8 families had the typical USH2 phenotype (congenital moderate to severe hearing impairment, normal vestibular function, and postpubertal onset of retinitis pigmentosa). However, 5 affected individuals from the remaining 4 families carrying the 2299delG mutation showed atypical Usher syndrome features, with progressive hearing impairment, variable vestibular function, and RP. An isolated patient with the mutation was typical of USH2 in all aspects, including nonprogressive hearing loss, but had absent vestibular function, which is a critical discriminator in clinical classification. Weston et al. (2000) revised numbering for the sequence of the USH2A gene, taking into account a significant sequence difference. The 2299delG mutation reported by Eudy et al. (1998) is correctly referred to as 2299delG. The sequence difference reduces the length of the usherin protein from 1551 to 1546 amino acids. Weston et al. (2000) found the 2299delG mutation to be the most frequent, having a frequency of 31 in 192 alleles (16%) in their series. Dreyer et al. (2001) presented data indicating that the widespread geographic distribution of the 2299delG mutation is the result of an ancestral mutation that spread throughout Europe and into the New World as a result of migration. Various studies had reported a range of frequencies (from 0.16 to 0.44) among patients with Usher syndrome, depending on the geographic origin of the patients. Dreyer et al. (2001) performed haplotype analysis on DNA samples from 116 unrelated patients with Usher syndrome type IIa; the patients were from 14 countries and represented 148 2299delG alleles. On the basis of 6 single-nucleotide polymorphisms (SNPs) within the USH2A gene, 12 core haplotypes were observed in a panel of normal chromosomes. However, in their patient analysis, only 1 core haplotype was associated with the 2299delG mutation. Ouyang et al. (2004) confirmed that 2299delG is the most common mutation in USH2A, accounting for 77.5% of the pathologic alleles. In 5 of the 24 patients, the 2299delG mutation was present in homozygous state; in 3 it was present in compound heterozygous state with other mutations; and in 16 it was present in heterozygous state. Baux et al. (2007) identified the 2299delG mutation, which results in a frameshift at codon 767, in 22% of mutated alleles in their study of 25 affected families. Yan et al. (2009) identified the 2299delG mutation in 38.9% of mutant alleles among 12 American probands of European descent with Usher syndrome type IIa. (less)
Pathogenic (Jan 30, 2015)	no assertion criteria provided Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals Accession: SCV000259101.1 First in ClinVar: Mar 25, 2016 Last updated: Mar 25, 2016	Publications: PubMed (1) PubMed: 26872967
Pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Usher syndrome Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000598800.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (2) PubMed: 28041643‚ 9624053 Observation 1: Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: NA Observation 2: Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: European Observation 3: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: European Observation 4: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: European Observation 5: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: European Observation 6: Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: European Observation 7: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: European
Pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000598799.1 First in ClinVar: May 03, 2013 Last updated: May 03, 2013	Publications: PubMed (2) PubMed: 28041643‚ 9624053 Observation 1: Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: NA Observation 2: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: European Observation 3: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: European Observation 4: Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: European Observation 5: Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: European
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Usher syndrome Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926729.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926730.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Macular dystrophy Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926911.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Cone-rod dystrophy Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926915.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Congenital stationary night blindness Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926917.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743802.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971183.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001979729.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (Apr 03, 2020)	no assertion criteria provided Method: clinical testing	Usher syndrome type 2A Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002093956.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Pathogenic (May 01, 2024)	no assertion criteria provided Method: clinical testing	USH2A-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004105974.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The USH2A c.2299delG variant is predicted to result in a frameshift and premature protein termination (p.Glu767Serfs21). This variant has been documented as causative for Usher … (more) The USH2A c.2299delG variant is predicted to result in a frameshift and premature protein termination (p.Glu767Serfs21). This variant has been documented as causative for Usher syndrome (Eudy et al. 1998. PubMed ID: 9624053; Aller et al. 2010. PubMed ID: 20145675; Aparisi et al. 2014. PubMed ID: 25404053). This variant is reported in 0.18% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in USH2A are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Sep 01, 2016)	no assertion criteria provided Method: clinical testing	Retinitis pigmentosa 39 Affected status: yes Allele origin: unknown	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Accession: SCV000804740.2 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015	Number of individuals with the variant: 1
Pathogenic (Aug 18, 2016)	no assertion criteria provided Method: clinical testing	Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000490146.2 First in ClinVar: Sep 29, 2015 Last updated: Dec 23, 2019	Publications: PubMed (2) PubMed: 24607488‚ 10909849
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001921682.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
not provided (-)	no classification provided Method: phenotyping only	USH2A-related disorder Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002074878.1 First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022	Comment: Variant interpreted as Pathogenic and reported on 06-28-2019 by Lab or GTR ID 500188. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Pathogenic and reported on 06-28-2019 by Lab or GTR ID 500188. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Premature birth (present) , Abnormal retinal morphology (present) , Hearing impairment (present) Indication for testing: Diagnostic Age: 30-39 years Sex: male Method: Sanger Sequencing Testing laboratory: Blueprint Genetics Date variant was reported to submitter: 2019-06-28 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: literature only	Retinitis pigmentosa Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000056187.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (3) PubMed: 10729113‚ 10909849‚ 20301515 BookShelf: NBK1341 BookShelf: NBK1341
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Comment:

The Glu767fs variant (rs80338903) has been observed in multiple cohorts of patients with Usher Syndrome, Type II (selected references: Eudy 1998, Dreyer 2001, Aller 2010). It is one of the most common pathogenic alleles of USH2A, and it is estimated that this variant accounts for 16% (Weston 2000) to 76% (Ouyang 2004) of all pathogenic USH2A variant. This variant is listed in the Genome Aggregation Database (gnomAD) database with a frequency in Latino populations of 0.20% (identified in 34 out of 34,442 chromosomes).

Comment:

Variant summary: USH2A c.2299delG (p.Glu767SerfsX21) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00076 in 250832 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher syndrome (0.00076 vs 0.013), allowing no conclusion about variant significance. c.2299delG has been reported in the literature in multiple individuals affected with Usher syndrome. This variant appears to be a common USH2A mutation contributing to Usher Syndrome Type II (e.g. Aller_2004, Calzetti_2018 and Gene Reviews). Lenassi et al suggest that this change could disrupt an exonic splicing enhancer and create an exonic splicing silencer within exon 13 and therefore affect splicing of exons 12 and 13 of USH2A (Lenassi_2014). Nine ClinVar submitters (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

NM_206933.2(USH2A):c.2299delG(aka E767Sfs*21) is classified as pathogenic in the context of USH2A-related disorders. Sources cited for classification include the following: PMID 10909849 and 24607488. Classification of NM_206933.2(USH2A):c.2299delG(aka E767Sfs*21)is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

Comment:

The USH2A c.2299del variant is classified as PATHOGENIC (PVS1, PS4, PM3) This USH2A c.2299del variant is located in exon 13/72 and is predicted to cause a shift in the reading frame at codon 767 (PVS1). This recurrent variant has been reported as the most common USH2A pathogenic variant (PMID: 20301515, PMID:9624053, PMID:22135276, PMID:24607488) (PS4). This variant has been detected in trans with another pathogenic variant for this recessive condition in both this individual and in other reported cases in the literature (PM3) and has also been reported as pathogenic in a homozygous state. This variant is in dbSNP (rs80338903) and has been reported as pathogenic for Usher syndrome and Retinitis pigmentosa by other diagnostic laboratories in ClinVar (ClinVar Variation ID: 2351) and in the disease database HGMD (CD982997).

Comment:

The c.2299delG (p.E767Sfs) variant is one of the most common pathogenic variants in USH2A and has been previously reported in multiple individuals with Usher syndrome type IIA or nonsyndromic retinitis pigmentosa (PMID: 18641288; 11402400; 15326663).

Comment:

The USH2A c.2299del 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, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic.

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22581970, 9624053, 32141364, 27344577, 20145675, 29847639, 23352160, 18665195, 26872967, 12525556, 11402400, 24607488, 29151245, 25097241, 15325563, 14970843, 26969326, 24160897, 25404053, 27460420, 22135276, 23924366, 17296898, 25649381, 24944099, 22495311, 21234346, 21174530, 11311042, 10775529, 10729113, 26633545, 10909849, 23891399, 20301515, 15025721, 12112664, 19881469, 17405132, 10090909, 30337596, 28157192, 28838317, 29953849, 31231422, 31266775, 32581362, 31827275, 31980526, 32176120, 32036094, 32664777, 31589614, 33576794, 30755392, 32853555)

Comment:

The p.Glu767SerfsTer21 variant in USH2A 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, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.

Comment:

The c.2299del;p.(Glu767Serfs*21) is a null frameshift variant (NMD) in the USH2A gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 2351; PMID: 20301515; 31836858; 30718709; 29953849;25649381; 25404053; 23924366; 12525556) - PS4. The variant is present at low allele frequencies population databases (rs80338903– gnomAD 0.04996%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Glu767Serfs*21) was detected in trans with a pathogenic variant (PMID: 31836858; 30718709; 29953849;25649381; 25404053; 23924366; 12525556) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 23924366; 12525556) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.070%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002351). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The USH2A c.2299del (p.Glu767SerfsTer21) variant results in the deletion of a nucleotide at position c.2299, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is predicted, though RNA expression studies performed on nasal epithelial cells suggest that the c.2299del variant could alternately disrupt splicing, leading to skipping of exon 13 or exons 12 and 13 (PMID: 24607488). The c.2299del variant is the most common disease-causing variant in the USH2A gene, and is estimated to account for over 20% of disease-causing alleles among individuals with Usher syndrome type 2, but has also been reported in individuals with non-syndromic retinitis pigmentosa (PMID: 9624053; PMID: 20301515, GeneReviews NBK1341; PMID: 25649381; PMID: 29953849; PMID: 36011334). The highest frequency of this allele in the Genome Aggregation Database is 0.001778 in the Latino/Admixed American population (version 2.1.1). Based on the available evidence, the c.2299del (p.Glu767SerfsTer21) variant is classified as pathogenic for Usher syndrome type 2.

Comment:

This sequence change creates a premature translational stop signal (p.Glu767Serfs*21) 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 (rs80338903, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with non-syndromic autosomal recessive retinitis pigmentosa and is a common Usher syndrome type II allele (PMID: 9624053, 11402400, 14970843, 15325563, 25097241, 25404053). This variant is also known as 2314delG. ClinVar contains an entry for this variant (Variation ID: 2351). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

The alteration results in a premature stop codon: _x000D_ _x000D_ The c.2299delG (p.E767Sfs*21) alteration, located in exon 13 (coding exon 12) of the USH2A gene, consists of a deletion of one nucleotide at position 2299, causing a translational frameshift with a predicted alternate stop codon after 21 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration has been observed in affected individuals:_x000D_ _x000D_ The c.2299delG alteration is the most common alteration found in Usher syndrome type II (Ouyang, 2004; Baux, 2007). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

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 Usher syndrome, type 2A (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (198 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported in patients with both retinitis pigmentosa and Usher syndrome (Decipher, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is one of the most common disease causing variants in the USH2A gene, and has been reported in patients with both Usher syndrome and retinitis pigmentosa (ClinVar, PMID: 29953849). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The USH2A c.2299delG variant is predicted to result in a frameshift and premature protein termination (p.Glu767Serfs*21). This variant has been documented as causative for Usher syndrome (Eudy et al. 1998. PubMed ID: 9624053; Aller et al. 2010. PubMed ID: 20145675; Aparisi et al. 2014. PubMed ID: 25404053). This variant is reported in 0.18% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in USH2A are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

Variant interpreted as Pathogenic and reported on 06-28-2019 by Lab or GTR ID 500188. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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
The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis.	Peter VG	PNAS nexus	2023	PMID: 36909829
Usher Syndrome Type II.	Adam MP	-	2023	PMID: 20301515
Phenotypic and Genetic Characteristics in a Cohort of Patients with Usher Genes.	Feenstra HM	Genes	2022	PMID: 36011334
The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK).	Zampaglione E	Genetics in medicine : official journal of the American College of Medical Genetics	2022	PMID: 34906470
Diagnostic yield of panel-based genetic testing in syndromic inherited retinal disease.	Jiman OA	European journal of human genetics : EJHG	2020	PMID: 31836858
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
Efficacy Outcome Measures for Clinical Trials of USH2A Caused by the Common c.2299delG Mutation.	Calzetti G	American journal of ophthalmology	2018	PMID: 29953849
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.	Carss KJ	American journal of human genetics	2017	PMID: 28041643
Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease.	Ellingford JM	Ophthalmology	2016	PMID: 26872967
Molecular diagnostic experience of whole-exome sequencing in adult patients.	Posey JE	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26633545
Whole USH2A Gene Sequencing Identifies Several New Deep Intronic Mutations.	Liquori A	Human mutation	2016	PMID: 26629787
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
Targeted next generation sequencing for molecular diagnosis of Usher syndrome.	Aparisi MJ	Orphanet journal of rare diseases	2014	PMID: 25404053
Dependable and efficient clinical utility of target capture-based deep sequencing in molecular diagnosis of retinitis pigmentosa.	Wang J	Investigative ophthalmology & visual science	2014	PMID: 25097241
Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots.	Baux D	Human mutation	2014	PMID: 24944099
The effect of the common c.2299delG mutation in USH2A on RNA splicing.	Lenassi E	Experimental eye research	2014	PMID: 24607488
Expressivity of hearing loss in cases with Usher syndrome type IIA.	Sadeghi AM	International journal of audiology	2013	PMID: 24160897
Screening for duplications, deletions and a common intronic mutation detects 35% of second mutations in patients with USH2A monoallelic mutations on Sanger sequencing.	Steele-Stallard HB	Orphanet journal of rare diseases	2013	PMID: 23924366
Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study.	Le Quesne Stabej P	Journal of medical genetics	2012	PMID: 22135276
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
The USH2A c.2299delG mutation: dating its common origin in a Southern European population.	Aller E	European journal of human genetics : EJHG	2010	PMID: 20145675
Mutation analysis in the long isoform of USH2A in American patients with Usher Syndrome type II.	Yan D	Journal of human genetics	2009	PMID: 19881469
Disease course in patients with autosomal recessive retinitis pigmentosa due to the USH2A gene.	Sandberg MA	Investigative ophthalmology & visual science	2008	PMID: 18641288
Molecular and in silico analyses of the full-length isoform of usherin identify new pathogenic alleles in Usher type II patients.	Baux D	Human mutation	2007	PMID: 17405132
Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa.	Seyedahmadi BJ	Experimental eye research	2004	PMID: 15325563
Mutational spectrum in Usher syndrome type II.	Ouyang XM	Clinical genetics	2004	PMID: 15025721
Genetic analysis of 2299delG and C759F mutations (USH2A) in patients with visual and/or auditory impairments.	Aller E	European journal of human genetics : EJHG	2004	PMID: 14970843
Mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa: high prevalence and phenotypic variation.	Bernal S	Journal of medical genetics	2003	PMID: 12525556
Iron dextran complex.	National Toxicology Program	Report on carcinogens : carcinogen profiles	2002	PMID: 15326663
Mutations in myosin VIIA (MYO7A) and usherin (USH2A) in Spanish patients with Usher syndrome types I and II, respectively.	Nájera C	Human mutation	2002	PMID: 12112664
A common ancestral origin of the frequent and widespread 2299delG USH2A mutation.	Dreyer B	American journal of human genetics	2001	PMID: 11402400
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
A mutation (2314delG) in the Usher syndrome type IIA gene: high prevalence and phenotypic variation.	Liu XZ	American journal of human genetics	1999	PMID: 10090909
Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa.	Eudy JD	Science (New York, N.Y.)	1998	PMID: 9624053
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A	-	-	-	-
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Text-mined citations for rs80338903 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_206933.4(USH2A):c.2299del (p.Glu767fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80338903 ...