Submissions for variant NM_206933.4(USH2A):c.8981G>A (p.Trp2994Ter)

gnomAD frequency: 0.00001  dbSNP: rs397518041

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041937	SCV000065633	pathogenic	Rare genetic deafness	2010-04-02	criteria provided, single submitter	clinical testing	The Trp2994X variant in USH2A has been reported in 2 probands with Usher syndrom e (Yan 2009). In addition, this variant leads to a premature stop codon at posit ion 2994 and therefore, is predicted to lead to a truncated or absent protein. I n summary, this variant meets our criteria to be classified as pathogenic (http: //pcpgm.partners.org/LMM).
Counsyl	RCV000666550	SCV000790858	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-04-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000760327	SCV000890183	pathogenic	not provided	2020-02-05	criteria provided, single submitter	clinical testing	Nonsense 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; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19881469, 28559085, 25525159, 28041643, 31266775)
Invitae	RCV000760327	SCV001201117	pathogenic	not provided	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp2994*) 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 (rs397518041, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 19881469, 28041643). ClinVar contains an entry for this variant (Variation ID: 48611). 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	RCV001075814	SCV001241450	pathogenic	Retinal dystrophy	2019-07-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193386	SCV001362169	pathogenic	Usher syndrome	2019-10-25	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.8981G>A (p.Trp2994X) 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 1.6e-05 in 251094 control chromosomes (gnomAD). c.8981G>A has been reported in the literature in individuals affected with Usher syndrome and retinitis pigmentosa (e.g. Carss_2017, Stone_2017, Yan_2009). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant twice as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376393	SCV001573514	pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.8981G>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. Based on this evidence we have classified this variant as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001273709	SCV003921792	pathogenic	Usher syndrome type 2A	2020-05-01	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 45 of 72). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. More than 10 NMD-predicted variants have been reported as likely pathogenic/pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in unrelated patients with Usher syndrome and retinitis pigmentosa (PMIDs: 19881469, 28041643), and as pathogenic in ClinVar. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Genome-Nilou Lab	RCV001376393	SCV004182749	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001273709	SCV004182750	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001376393	SCV004208166	pathogenic	Retinitis pigmentosa 39	2024-03-24	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504790	SCV000598838	pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Natera, Inc.	RCV001273709	SCV001457079	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing