Submissions for variant NM_206933.2(USH2A):c.3902G>T (p.Gly1301Val)

gnomAD frequency: 0.00008  dbSNP: rs111033524

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000787994	SCV000927022	benign	Usher syndrome	2024-03-20	reviewed by expert panel	curation	The c.3902G>T variant in USH2A is a missense variant predicted to cause substitution of glycine by valine at amino acid 1301 (p.Gly1301Val). The highest population filtering allele frequency with a confidence interval of 0.95 in gnomAD v4.0.0 is 0.5% (469/91078) with 4 homozygotes in the South Asian population, which meets the ClinGen Hearing Loss VCEP criteria for BA1 (>=0.5%). The computational predictor REVEL gives a score of 0.218, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. While this variant has been reported in several individuals with clinical features of USH2A-related disorders, there are no case-control studies and several affected individuals had an alternate cause of disease identified (PMID:21569298, 25649381, 26927203, 32531858). In summary, this variant meets the criteria to be classified as benign, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BA1, ClinGen Hearing Loss VCEP specifications version 2, 03.20.2024).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041835	SCV000065531	likely benign	not specified	2010-04-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000488230	SCV000574821	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	USH2A: BP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000488230	SCV000884865	uncertain significance	not provided	2018-06-22	criteria provided, single submitter	clinical testing	The USH2A c.3902G>T; p.Gly1301Val variant (rs111033524) is reported in the medical literature in individuals with Usher syndrome and retinitis pigmentosa, however, one of these individuals also carried an alternate molecular explanation for disease (Bonnet 2011, Pierrache 2016). The variant is reported with discrepant classifications in the ClinVar database (Variation ID: 48509) and in the Genome Aggregation Database in 0.6% (184/30778 alleles) of the South Asian population. The glycine at this codon is moderately conserved but computational analyses (SIFT:Tolerated, PolyPhen-2: Probably Damaging) predict conflicting effects of this variant on protein structure/function. Although there is information indicating this variant may not be pathogenic, there is insufficient evidence to classify the variant with certainty. Pathogenic USH2A variants are causative for autosomal recessive Usher syndrome (MIM: 276901) and retintitis pigmentosa (MIM: 613809). References: Bonnet C et al. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis. Orphanet J Rare Dis. 2011 May 11;6:21. Pierrache LH et al. Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa. Ophthalmology. 2016 May;123(5):1151-60.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000488230	SCV001039111	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000986538	SCV001135556	benign	Usher syndrome type 2A	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000505069	SCV001259149	uncertain significance	Retinitis pigmentosa	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000986538	SCV001259150	uncertain significance	Usher syndrome type 2A	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376513	SCV001573690	benign	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.3902G>T 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: BP5, BA1, PP3. Based on this evidence we have classified this variant as Benign.
Genome-Nilou Lab	RCV000986538	SCV001737304	benign	Usher syndrome type 2A	2021-06-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001376513	SCV001806339	benign	Retinitis pigmentosa 39	2021-07-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000488230	SCV002504115	likely benign	not provided	2019-01-17	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Fulgent Genetics, Fulgent Genetics	RCV002496665	SCV002809626	likely benign	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-04-20	criteria provided, single submitter	clinical testing
GeneReviews	RCV000219904	SCV000268767	likely pathogenic	Usher syndrome type 1	2016-05-19	flagged submission	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505069	SCV000598808	likely pathogenic	Retinitis pigmentosa	2015-01-01	flagged submission	research
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	RCV000787994	SCV003927074	likely pathogenic	Usher syndrome	2022-12-31	flagged submission	research
PreventionGenetics, part of Exact Sciences	RCV004537151	SCV004754830	likely benign	USH2A-related disorder	2022-09-23	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).