Submissions for variant NM_206933.4(USH2A):c.908G>A (p.Arg303His)

gnomAD frequency: 0.00004  dbSNP: rs371777049

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000276147	SCV000337027	pathogenic	not provided	2015-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000276147	SCV001224324	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 303 of the USH2A protein (p.Arg303His). This variant is present in population databases (rs371777049, gnomAD 0.006%). This missense change has been observed in individual(s) with Usher syndrome and retinitis pigmentosa (PMID: 19881469, 25342620, 28157192). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 284411). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt USH2A protein function with a negative predictive value of 95%. This variant disrupts the p.Arg303 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 14970843, 28157192), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074790	SCV001240386	pathogenic	Retinal dystrophy	2019-07-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000276147	SCV001250065	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000276147	SCV001766817	pathogenic	not provided	2020-10-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24944099, 25342620, 22004887, 21569298, 28157192, 31766479, 30872814, 19881469)
Revvity Omics, Revvity	RCV000276147	SCV002020844	pathogenic	not provided	2021-06-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000666542	SCV002072515	likely pathogenic	Retinitis pigmentosa 39	2022-01-05	criteria provided, single submitter	clinical testing	This variant was identified as homozygous._x000D_ Criteria applied: PM3_STR, PM5, PM2_SUP, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002229842	SCV002511995	pathogenic	Usher syndrome	2022-04-27	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.908G>A (p.Arg303His) results in a non-conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250388 control chromosomes. c.908G>A has been reported in the literature in multiple individuals affected with Usher Syndrome (example, Sanchez-Alcudia_2014, Weisschuh_2020, Schrauwen_2019, Bonnet_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000666542	SCV004182929	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001828199	SCV004182930	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000666542	SCV004207707	pathogenic	Retinitis pigmentosa 39	2024-02-20	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001828199	SCV005051991	pathogenic	Usher syndrome type 2A	2024-02-01	criteria provided, single submitter	curation
Counsyl	RCV000666542	SCV000790848	likely pathogenic	Retinitis pigmentosa 39	2017-04-12	no assertion criteria provided	clinical testing
Center for Statistical Genetics, Columbia University	RCV000754554	SCV000853292	pathogenic	Hearing impairment	2018-10-08	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000754554	SCV001439132	likely pathogenic	Hearing impairment		no assertion criteria provided	research
Natera, Inc.	RCV001828199	SCV002094008	pathogenic	Usher syndrome type 2A	2020-11-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732821	SCV005366399	pathogenic	USH2A-related disorder	2024-06-25	no assertion criteria provided	clinical testing	The USH2A c.908G>A variant is predicted to result in the amino acid substitution p.Arg303His. This variant has been reported in the compound heterozygous state with a pathogenic or likely pathogenic USH2A variant in multiple individuals with Usher Syndrome (Yan et al. 2009. PubMed ID: 19881469; Bonnet et al. 2011. PubMed ID: 21569298; Garcia-Garcia et al. 2011. PubMed ID: 22004887; Baux et al. 2014. PubMed ID: 24944099; Sanchez-Alcudia et al. 2014. PubMed ID: 25342620; Bravo-Gil et al. 2017. PubMed ID: 28157192; Eandi et al. 2017. PubMed ID: 29142287). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been classified as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar databse (https://www.ncbi.nlm.nih.gov/clinvar/variation/284411/). Given the evidence, we interpret this variant as pathogenic.