Submissions for variant NM_206933.4(USH2A):c.9570+1G>A

gnomAD frequency: 0.00004  dbSNP: rs760225886

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217703	SCV000271476	pathogenic	Rare genetic deafness	2015-04-17	criteria provided, single submitter	clinical testing	The c.9570+1G>A variant in USH2A has been reported in 4 Chinese individuals: 2 w ith Usher syndrome, 1 with hearing loss, and 1 with retinitis pigmentosa, and se gregated with disease in at least 3 affected individuals from 3 families (Huang 2013, Yang 2013, Xu 2014, Qu 2014). All of these individuals were compound hete rozygous. In addition, this variant has been identified in 7/8606 of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org). Although this variant has been seen in the general population, its freq uency is low enough to be consistent with a recessive carrier frequency. The c.9 570+1G>A variant occurs in the invariant region (+/- 1,2) of the splice consensu s sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive Usher syndrome (www.partners.org/personalized medicine/lmm).
Invitae	RCV000808044	SCV000948130	pathogenic	not provided	2023-11-04	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 48 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 (rs760225886, gnomAD 0.06%). Disruption of this splice site has been observed in individual(s) with Usher syndrome and USH2A-related diseases (PMID: 23737954, 23767834, 24938718). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS48+1G>A. ClinVar contains an entry for this variant (Variation ID: 228418). 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	RCV001073320	SCV001238859	pathogenic	Retinal dystrophy	2018-11-20	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000666079	SCV001573408	pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.9570+1G>A 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, PP3, PP1-M. Based on this evidence we have classified this variant as Pathogenic.
GeneDx	RCV000808044	SCV001821035	pathogenic	not provided	2023-04-24	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24938718, 23767834, 23737954, 25252889, 30948794, 33111992, 32188678, 34130719, 32675063)
3billion	RCV001808577	SCV002058386	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: VCV000228418). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000040, PM2_M). The variant has been reported to be in trans with a pathogenic variant (NM_206933.4:c.2187C>A) as compound heterozygous (3billion dataset, PM3_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Pangenia Genomics, Pangenia Inc.	RCV000666079	SCV003922395	pathogenic	Retinitis pigmentosa 39	2021-11-18	criteria provided, single submitter	research	The USH2A, c.9570+1G>A variant is at a canonical ±1 or 2 splice site, resulting in a null variant. This variant is at extremely low frequency in population database; allele frequency in East Asia population is 0.0005 by gnomAD v2.1.1. This variant is detected in trans with a pathogenic variant [USH2A, c.2802T>G (p.Cys934Trp)]. This variant has been previously reported to be detected in a deaf patient (Usher syndrome), in trans with c.1992_1993insT [PMID: 23767834] and in another two Usher syndrome patients who are from the same family, in trans with c.8559-2A>G [PMID: 25252889]. There is co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. This variant has been reported to co-segregate with Usher syndrome or RP in at least 4 families [PMID: 23737954, 24938718, 25252889, 3094874]. There are multiple submissions of this variant in ClinVar (Variation ID: 228418), all rated as Pathogenic.
Genome-Nilou Lab	RCV000666079	SCV004172037	pathogenic	Retinitis pigmentosa 39	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001808577	SCV004172038	pathogenic	Usher syndrome type 2A	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000666079	SCV004208262	pathogenic	Retinitis pigmentosa 39	2023-09-14	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV001073320	SCV004707907	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV003937848	SCV004751964	pathogenic	USH2A-related condition	2023-11-15	criteria provided, single submitter	clinical testing	The USH2A c.9570+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in as causative in patients with autosomal recessive Usher syndrome, retinitis pigmentosa or nonsyndromic hearing loss (Qu. 2014. PubMed ID: 25252889; Yang. 2013. PubMed ID: 23767834; Xu. 2014. PubMed ID: 24938718). This variant is reported in 0.054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-215990338-C-T). Variants that disrupt the consensus splice donor site in USH2A are expected to be pathogenic. This variant is interpreted as pathogenic.
Counsyl	RCV000666079	SCV000790318	pathogenic	Retinitis pigmentosa 39	2017-03-13	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001808577	SCV002088396	pathogenic	Usher syndrome type 2A	2020-12-09	no assertion criteria provided	clinical testing