Submissions for variant NM_206933.4(USH2A):c.5776+1G>A

gnomAD frequency: 0.00001  dbSNP: rs876657731

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213465	SCV000271472	pathogenic	Rare genetic deafness	2015-04-02	criteria provided, single submitter	clinical testing	The c.5776+1G>A variant in USH2A has been previously reported in 12 individuals: 9 with Usher syndrome and 2 with retinitis pigmentosa (Baux 2014, Dreyer 2008, Glockle 2014, Jaijo 2010, Lenarduzzi 2015, Lenassi 2015, Sandberg 2008, Sodi 201 4, Wang 2014). Ten of these individuals were either compound heterozygous or hom ozygous for the variant. This variant has not been reported in large population studies. The c.5776+1G>A variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, analysis of mRNA extracted from a c arrier of the c.5776+1G>A variant showed in-frame skipping of exon 28 (Lenassi 2 015), confirming a splicing impact. In summary, this variant meets our criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive mann er (www.partners.org/personalizedmedicine/lmm) based upon its identification in the homozygous or compound heterozygous state in multiple affected individuals a nd the reported impact on splicing.
GeneDx	RCV000255459	SCV000321998	pathogenic	not provided	2022-12-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 26355662, 23591405, 29074561, 32531858, 25097241, 25649381, 34758253, 32188678, 31589614, 32552793, 32176120, 18273898, 24944099, 25558175, 25575603, 29490346, 19683999, 18641288, 31456290, 34426522, 33576794, 32037395, 34781295, 35266249)
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV001002706	SCV001156362	pathogenic	Usher syndrome type 2A	2019-02-01	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074367	SCV001239943	pathogenic	Retinal dystrophy	2019-07-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000255459	SCV001247003	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375185	SCV001571791	pathogenic	Usher syndrome	2021-04-12	criteria provided, single submitter	clinical testing	PVS1_Strong, PS1_Strong, PM2_Moderate, PM3_Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255459	SCV001590592	pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 28 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (no rsID available, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with Usher syndrome or retinitis pigmentosa (PMID: 25097241, 26355662, 29490346). ClinVar contains an entry for this variant (Variation ID: 228414). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001723796	SCV001950392	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The c.5776+1G>A 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, 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.
3billion	RCV001002706	SCV002059192	pathogenic	Usher syndrome type 2A	2022-01-03	criteria provided, single submitter	clinical testing	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000228414). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Myriad Genetics, Inc.	RCV001002706	SCV002060022	pathogenic	Usher syndrome type 2A	2021-11-08	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.5776+1G>A is a canonical splice variant classified as pathogenic in the context of USH2A-related disorders. c.5776+1G>A has been observed in cases with relevant disease (PMID: 25575603, 19683999). Functional assessments of this variant are available in the literature (PMID: 25649381). c.5776+1G>A has been observed in population frequency databases (gnomAD: NFE 0.002%). In summary, NM_206933.2(USH2A):c.5776+1G>A is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
AiLife Diagnostics, AiLife Diagnostics	RCV000255459	SCV002502724	pathogenic	not provided	2022-03-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500705	SCV002812875	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-03-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001542730	SCV004172118	pathogenic	Retinitis pigmentosa 39	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001002706	SCV004172119	pathogenic	Usher syndrome type 2A	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001542730	SCV004208264	pathogenic	Retinitis pigmentosa 39	2024-02-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255459	SCV004238392	pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375185	SCV004241187	pathogenic	Usher syndrome	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.5776+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, showing the variant causes exon skipping resulting in a shortened mRNA product in a minigene assay (Fuster-Garcia_2018). The variant allele was found at a frequency of 1.2e-05 in 250072 control chromosomes. c.5776+1G>A has been reported in the literature in multiple individuals affected with Usher Syndrome, including as a homozygous phenotype (e.g. Fuster-Garcia_2018, Glockle_2014). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30459346, 23591405). 16 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001002706	SCV004804949	pathogenic	Usher syndrome type 2A	2024-03-17	criteria provided, single submitter	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003271	SCV001161354	pathogenic	Usher syndrome type 2	2019-06-23	no assertion criteria provided	research
Faculty of Health Sciences, Beirut Arab University	RCV001257907	SCV001434723	pathogenic	Autosomal recessive retinitis pigmentosa	2015-09-10	no assertion criteria provided	literature only
Natera, Inc.	RCV001002706	SCV001462252	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV001542730	SCV001760017	likely pathogenic	Retinitis pigmentosa 39		no assertion criteria provided	clinical testing