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

gnomAD frequency: 0.00055  dbSNP: rs80338903

Total submissions: 53

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824793	SCV000065508	pathogenic	Usher syndrome; Rare genetic deafness	2014-09-30	criteria provided, single submitter	clinical testing	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).
Eurofins Ntd Llc (ga)	RCV000254870	SCV000225952	pathogenic	not provided	2016-10-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000191141	SCV000245550	pathogenic	Retinitis pigmentosa 39	2024-03-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000254870	SCV000321994	pathogenic	not provided	2020-01-13	criteria provided, single submitter	clinical testing	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)
Ambry Genetics	RCV000623326	SCV000740743	pathogenic	Inborn genetic diseases	2020-03-03	criteria provided, single submitter	clinical testing	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.
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735362	SCV000854516	pathogenic	Short stature; Cognitive impairment; High palate; Distal arthrogryposis; Anxiety; Brisk reflexes; Abnormal autonomic nervous system physiology; Abnormality of the upper limb; Multiple joint contractures; Dislocated radial head; Abnormality of upper limb joint; Chronic pain; Abnormal upper limb bone morphology		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000254870	SCV000940875	pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	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.
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000002445	SCV001156376	pathogenic	Usher syndrome type 2A	2019-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000453	SCV001157289	pathogenic	not specified	2018-07-31	criteria provided, single submitter	clinical testing	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).
Baylor Genetics	RCV000002445	SCV001162881	pathogenic	Usher syndrome type 2A		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000002445	SCV001194141	pathogenic	Usher syndrome type 2A	2019-12-17	criteria provided, single submitter	clinical testing	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.
Blueprint Genetics	RCV000210326	SCV001239242	pathogenic	Retinal dystrophy	2019-08-15	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000002445	SCV001244816	pathogenic	Usher syndrome type 2A	2023-07-17	criteria provided, single submitter	clinical testing	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
CeGaT Center for Human Genetics Tuebingen	RCV000254870	SCV001248858	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	USH2A: PM3:Very Strong, PVS1, PP1:Strong, PM2
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV001095692	SCV001251499	pathogenic	USH2A-related disorder		criteria provided, single submitter	research	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504641	SCV001362171	pathogenic	Usher syndrome	2019-10-25	criteria provided, single submitter	clinical testing	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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000254870	SCV001446853	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000254870	SCV001448876	pathogenic	not provided	2017-09-26	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000191141	SCV001573518	pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	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.
Genomics England Pilot Project, Genomics England	RCV000002445	SCV001760021	pathogenic	Usher syndrome type 2A		criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV000191141	SCV001760022	pathogenic	Retinitis pigmentosa 39		criteria provided, single submitter	clinical testing
DBGen Ocular Genomics	RCV000002445	SCV001816033	pathogenic	Usher syndrome type 2A	2021-06-28	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000032524	SCV001950408	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	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.
Revvity Omics, Revvity	RCV000254870	SCV002020836	pathogenic	not provided	2021-11-24	criteria provided, single submitter	clinical testing
DASA	RCV001095692	SCV002061238	pathogenic	USH2A-related disorder	2022-01-05	criteria provided, single submitter	clinical testing	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.
3billion	RCV000191141	SCV002521582	pathogenic	Retinitis pigmentosa 39	2022-05-22	criteria provided, single submitter	clinical testing	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.
Genetics and Molecular Pathology, SA Pathology	RCV000002445	SCV002761479	pathogenic	Usher syndrome type 2A	2022-04-07	criteria provided, single submitter	clinical testing	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).
Fulgent Genetics, Fulgent Genetics	RCV002504737	SCV002805172	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-03-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000002445	SCV004014655	pathogenic	Usher syndrome type 2A	2023-01-11	criteria provided, single submitter	clinical testing	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.
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV000504641	SCV004030341	pathogenic	Usher syndrome	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Institute of Human Genetics, University of Leipzig Medical Center	RCV000002445	SCV004032322	pathogenic	Usher syndrome type 2A	2024-04-09	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000191141	SCV004182441	pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000002445	SCV004182442	pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000002445	SCV005200866	pathogenic	Usher syndrome type 2A	2024-06-10	criteria provided, single submitter	clinical testing	PVS1, PS3, PM3_Very Strong, PM6
OMIM	RCV000002445	SCV000022603	pathogenic	Usher syndrome type 2A	2009-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000032524	SCV000056187	not provided	Retinitis pigmentosa		no assertion provided	literature only
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000210326	SCV000259101	pathogenic	Retinal dystrophy	2015-01-30	no assertion criteria provided	clinical testing
Counsyl	RCV000191141	SCV000490146	pathogenic	Retinitis pigmentosa 39	2016-08-18	no assertion criteria provided	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000032524	SCV000598799	pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504641	SCV000598800	pathogenic	Usher syndrome	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000191141	SCV000804740	pathogenic	Retinitis pigmentosa 39	2016-09-01	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000504641	SCV000926729	pathogenic	Usher syndrome	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000032524	SCV000926730	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787895	SCV000926911	pathogenic	Macular dystrophy	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787897	SCV000926915	pathogenic	Cone-rod dystrophy	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787899	SCV000926917	pathogenic	Congenital stationary night blindness	2018-04-01	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000254870	SCV001743802	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000254870	SCV001921682	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000254870	SCV001971183	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000254870	SCV001979729	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV001095692	SCV002074878	not provided	USH2A-related disorder		no assertion provided	phenotyping only	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.
Natera, Inc.	RCV000002445	SCV002093956	pathogenic	Usher syndrome type 2A	2020-04-03	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001095692	SCV004105974	pathogenic	USH2A-related disorder	2024-05-01	no assertion criteria provided	clinical testing	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.