Submissions for variant NM_206933.4(USH2A):c.1841-2A>G (rs397518003)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000041799	SCV000065495	pathogenic	Rare genetic deafness	2018-12-04	criteria provided, single submitter	clinical testing	The c.1841-2A>G variant in USH2A has been reported in at least 12 probands with Usher syndrome and 2 probands with retinitis pigmentosa (RP), including at least 3 homozygous individuals and 7 individuals who were compound heterozygous for a second pathogenic USH2A variant (Bernal 2003, Maubaret 2005, Sandberg 2008, Jai jo 2010, Garcia-Garcia 2011, Vozzi 2011, LeQuesne Stabej 2012, Sodi 2014, Lenard uzzi 2015, Bonnet 2016, LMM data). This variant segregated with RP in one affect ed sibling (Bernal 2003). It has also been identified in 0.003% (4/113596) of Eu ropean chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this f requency is low enough to be consistent with a recessive carrier frequency. Fina lly, the c.1841-2A>G variant is located in the canonical splice consensus sequen ce and functional studies demonstrate that it causes skipping of exon 11, leadin g to a frameshift and the introduction of a premature termination codon (Jaijo 2 011). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP criteria applied: PVS1, PM3_VerySt rong, PM2, PP4.
Illumina Clinical Services Laboratory,Illumina	RCV000270130	SCV000354157	pathogenic	USH2A-Related Disorders	2017-04-28	criteria provided, single submitter	clinical testing	The USH2A c.1841-2A>G occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1841-2A>G variant has been reported in ten studies in which it is found in a total of 14 individuals including five homozygotes, two compound heterozygotes and five heterozygotes with Usher syndrome, and two compound heterozygotes with autosomal recessive retinitis pigmentosa (Bernal et al. 2003; Maubaret et al. 2005; Sandberg et al. 2008; Jaijo et al. 2010; Jaijo et al. 2011; Garcia-Garcia et al. 2011; Vozzi et al. 2011; Le Quesne Stabej et al. 2012; Baux et al. 2014). The variant was also observed in a homozygous state in two siblings with non-syndromic hearing loss in whom no visual phenotype was reported (Vona et al. 2014). The variant was shown to co-segregate with autosomal recessive retinitis pigmentosa in one family (Bernal et al. 2003; Sandberg et al. 2008). The c.1841-2A>G variant was absent from 1272 control chromosomes and is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Using minigene assays the c.1841-2A>G variant was shown to cause skipping of exon 11 and an r.1841_1971del change at the RNA level, leading to a frameshift (p.Gly614AspfsX6) with premature truncation and the loss of approximately 88% of the protein. Based on the collective evidence and potential impact of splice acceptor variants, the c.1841-2A>G variant is classified as pathogenic for USH2A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics,Fulgent Genetics	RCV000665036	SCV000893961	pathogenic	Usher syndrome, type 2A; Retinitis pigmentosa 39	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001069761	SCV001234953	pathogenic	not provided	2020-10-22	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 10 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 (rs397518003, ExAC 0.004%). This variant has been observed in individual(s) with USH2A-related conditions (PMID: 12525556, 27460420, 29986705). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48476). Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (PMID: 20497194). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV001069761	SCV001248861	pathogenic	not provided	2017-10-01	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000984014	SCV001573710	pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.1841-2A>G 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, PS3, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic.
INGEBI, INGEBI / CONICET	RCV001544537	SCV001763583	pathogenic	Nonsyndromic hearing loss and deafness	2021-07-15	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.1841-2 A>G variant in USH2A gene has benn found in 4/113596 alleles only in european non-finnish population (0.0012% with 95% CI) meeting PM2 rule . This type of variant is predicted to generate a lost of the acceptor splicing site in USH2A gene , which is a known mechanism of disease, PVS1. The c.1841-2 A>G has been identified in trans with different pathogenic variants in at least 10 individuals (PM3_VS): 2 patients with retinitis pigmentosa, 9 cases of type 2 Usher patients (PP4), one type 3 Usher patient and 3 hearing loss patients (variants detected in early childhood); (PMID:12525556, 18641288, 19683999, 21738395, 22004887, 22135276, 24875298, 24944099, 25558175, 25575603, 29986705, 27460420, this report). The c.1841-2 A>G segregated correctly in two familial cases: one family composed of two siblings with retinitis pigmentosa and two unaffected siblings and a second familiy case composed of two siblings with hearing loss (PMID: 12525556, 24875298) applying to PP1_Mod. Functional studies in COS-7 cells using minigen system demonstrated that this variant generated the skippining of exon 11 leading to a freamshift: p.Gly614Aspfs6* (PMID20497194); PS3_Supp.Considering PM2, PVS1_VS, PP4, PP1_M, PS3_S the variant is classfied as Pathogenic for Usher Syndrome and retinitis pigmentosa.
GeneDx	RCV001069761	SCV001805256	pathogenic	not provided	2020-10-20	criteria provided, single submitter	clinical testing	Observed with a second USH2A variant in many patients with Usher syndrome or hearing loss in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Sandberg et al., 2008; Vozzi et al., 2011; Zhang et al., 2016; Bonnet et al., 2016; Cabanillas et al., 2018); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33576794, 31589614, 32037395, 32036094, 31736247, 24875298, 27596865, 15823922, 19683999, 18641288, 21738395, 29986705, 31231422, 28559085, 24944099, 21569298, 22135276, 21487335, 27460420, 12525556, 25525159, 22004887, 20497194)
Counsyl	RCV000984014	SCV000789092	pathogenic	Retinitis pigmentosa 39	2017-01-19	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001271238	SCV001452254	pathogenic	Usher syndrome, type 2A	2020-09-16	no assertion criteria provided	clinical testing