Submissions for variant NM_206933.4(USH2A):c.8559-2A>G

gnomAD frequency: 0.00003  dbSNP: rs397518039

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000710341	SCV000840538	pathogenic	Usher syndrome	2018-10-09	reviewed by expert panel	curation	The c.8559-2A>G has been detected in >4 patients with Usher syndrome who were compound heterozygous for the this variant in trans with a truncating variant (PM3_VS; PMID: 25356976, 19737284, 26338283, 19023448). Segregation data was also available for two reported families with Usher syndrome. In one family, the variant was identified in trans with a frameshift variant in two affected siblings, and four unaffected siblings were either heterozygous for a single variant or wild-type for both variants. In the second family, an unaffected sibling was heterozygous for a single variant (PP1_Strong, PMID: 19023448). RT-PCR analysis of cells from a patient carrying the variant revealed that the variant causes skipping of exon 43, resulting in a 41 amino acid deletion of the USH2A protein (PM4, PMID: 20596040) The allele frequency of the c.8559-2A>G variant in the USH2A gene is 0.046% (8/17232) of East Asian chromosomes by the Genome Aggregation Database ( http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss and Usher syndrome (PM2_Supporting). Several patients reported to harbor this variant displayed clinical features of Usher syndrome (PP4; PMID: 25356976, 19737284, 26338283, 19023448). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM4, PM3_VS, PP1_S, PP4, PM2_P.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824785	SCV000065626	pathogenic	Rare genetic deafness	2011-09-12	criteria provided, single submitter	clinical testing	The 8559-2A>G variant in USH2A has been reported in 6 Asian individuals with Ush er type 2 and was absent in 470 Asian control chromosomes (Dai 2008, Nakanishi 2 009). All of these probands were compound heterozygous. This variant is predicte d to cause abnormal splicing because the nucleotide substitution occurs in the i nvariant region of the splice consensus sequence. Furthermore, RT-PCR analysis o f cells from a patient carrying the variant revealed that the variant causes ski pping of exon 43, resulting in a 41 amino acid deletion of the USH2A protein (Na kanishi 2010). In summary, this variant meets our criteria to be classified as p athogenic.
Eurofins Ntd Llc (ga)	RCV000592589	SCV000700946	pathogenic	not provided	2017-01-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000665497	SCV000893286	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-04-20	criteria provided, single submitter	clinical testing
Invitae	RCV000592589	SCV000938861	pathogenic	not provided	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 42 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 (rs397518039, gnomAD 0.05%). Disruption of this splice site has been observed in individuals with Usher syndrome (PMID: 19023448, 19737284). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48604). 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.
Blueprint Genetics	RCV001075171	SCV001240783	pathogenic	Retinal dystrophy	2018-10-19	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000592589	SCV001762245	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
3billion	RCV000041930	SCV002059155	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 multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000048604, 3billion dataset). The variant was co-segregated with Usher syndrome, type 2A in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 19023448, PP1_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000032, PM2_M). The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 19737284, 26338283, 25356976, 19023448, PM3_VS). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Myriad Genetics, Inc.	RCV000041930	SCV002060359	pathogenic	Usher syndrome type 2A	2021-11-09	criteria provided, single submitter	clinical testing	NM_206933.2(USH2A):c.8559-2A>G is a canonical splice site variant classified as pathogenic in the context of USH2A-related disorders. c.8559-2A>G has been observed in cases with relevant disease (PMID: 25324289, 20596040, 25356976). Functional assessments of this variant are available in the literature (PMID: 20596040). c.8559-2A>G has been observed in population frequency databases (gnomAD: EAS 0.05%). In summary, NM_206933.2(USH2A):c.8559-2A>G is a canonical splice site 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.
Revvity Omics, Revvity	RCV000592589	SCV003826086	pathogenic	not provided	2022-05-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460553	SCV004208226	pathogenic	Retinitis pigmentosa 39	2023-09-30	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV001075171	SCV004707924	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Department of Ophthalmology and Visual Sciences Kyoto University	RCV000132715	SCV000172669	pathogenic	Retinitis pigmentosa		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000041930	SCV000902401	pathogenic	Usher syndrome type 2A	2019-02-26	no assertion criteria provided	case-control
Natera, Inc.	RCV000041930	SCV001458111	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing