Submissions for variant NM_206933.4(USH2A):c.1000C>T (p.Arg334Trp)

gnomAD frequency: 0.00003  dbSNP: rs397517963

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213203	SCV000271469	pathogenic	Rare genetic deafness	2015-04-27	criteria provided, single submitter	clinical testing	The p.Arg334Trp variant in USH2A has been reported in 9 probands with Usher synd rome who were either compound heterozygous or homozygous, and segregated in 9 fa mily members (Adato 2000, Auslender 2008, Baux 2014, Baux 2007, Dreyer 2000, Jai jo 2009, Krawitz 2014, Ouyang 2004). This variant has been identified in 4/11496 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs397517963), however this frequency is low enough to be co nsistent with a recessive carrier frequency. In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive Usher syndrome b ased on multiple reports with pathogenic USH2A variants in individuals with Ushe r syndrome (http://personalizedmedicine.partners.org/).
Counsyl	RCV000668930	SCV000793608	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-08-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000822071	SCV000962856	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 334 of the USH2A protein (p.Arg334Trp). This variant is present in population databases (rs397517963, gnomAD 0.03%). This missense change has been observed in individuals with Usher syndrome (PMID: 10909849, 15025721, 17405132, 18452394, 19683999, 20513143, 25333064, 26338283, 27032803, 28894305, 28944237, 29142287). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228411). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. This variant disrupts the p.Arg334 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 17405132), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074876	SCV001240480	pathogenic	Retinal dystrophy	2019-08-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000822071	SCV001982941	pathogenic	not provided	2024-02-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33124170, 32675063, 34781295, 17405132, 10738000, 10909849, 19683999, 25333064, 15025721, 24944099, 26338283, 27032803, 29490346, 31589614, 31456290, 32050993, 18452394, 32531858)
Genome-Nilou Lab	RCV003454598	SCV004182918	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001273812	SCV004182919	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003454598	SCV004208187	pathogenic	Retinitis pigmentosa 39	2024-03-26	criteria provided, single submitter	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003287	SCV001161370	pathogenic	Usher syndrome type 2	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV001273812	SCV001457325	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing