Submissions for variant NM_206933.4(USH2A):c.9459C>A (p.Cys3153Ter)

dbSNP: rs73090721

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041954	SCV000065650	pathogenic	Rare genetic deafness	2012-03-12	criteria provided, single submitter	clinical testing	The Cys3153X variant in USH2A has been reported in one individual with Usher syn drome who was compound heterozygous with a second pathogenic USH2A variant (Le Q uesne Stabej 2012). This nonsense variant leads to a premature termination codon at position 3153, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http ://pcpgm.partners.org/LMM).
Counsyl	RCV000674717	SCV000800106	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2018-05-22	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001075710	SCV001241338	pathogenic	Retinal dystrophy	2019-04-24	criteria provided, single submitter	clinical testing
Invitae	RCV001388971	SCV001590165	pathogenic	not provided	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys3153*) 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 (rs73090721, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with clinical features of Usher syndrome and/or retinitis pigmentosa (PMID: 22135276, 28559085, 31370859). ClinVar contains an entry for this variant (Variation ID: 48628). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001388971	SCV001778423	pathogenic	not provided	2021-08-01	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: 22135276, 28894305, 31266775, 28559085, 26164827, 31370859)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778686	SCV002015092	pathogenic	Usher syndrome	2021-10-27	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.9459C>A (p.Cys3153X) 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 was absent in 250418 control chromosomes (gnomAD). c.9459C>A has been reported in the literature in individuals affected with Usher Syndrome and autosomal recessive Retinitis Pigmentosa (e.g. Le Quesne Stabej_2012, Sujirakul_2015). 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. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	RCV001778686	SCV003927108	pathogenic	Usher syndrome	2022-12-31	criteria provided, single submitter	research
Genome-Nilou Lab	RCV003450911	SCV004182689	pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001273702	SCV004182690	pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001273702	SCV001457071	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing