Submissions for variant NM_206933.4(USH2A):c.11156G>A (p.Arg3719His)

gnomAD frequency: 0.00006  dbSNP: rs527236139

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413588	SCV000490871	pathogenic	not provided	2024-03-29	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: 31736247, 28041643, 29641573, 27460420, 28157192, 34416374, 32531858, 20507924, 29899460, 25133613, 26496393, 25324289, 26927203, 30280194, 28559085, 29625443, 30190494, 30718709, 31054281, 32100970, 32581362, 32188678, 33105608, 34426522, 33124170, 32675063, 33090715, 33691693, 33946315, 34721897, 31960602, 32637036, 34839010, 31269850, 25649381, 35266249, 32037395, 36819107, 37217505, 36460718, 36729443)
Counsyl	RCV000665160	SCV000789229	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-01-20	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074730	SCV001240323	pathogenic	Retinal dystrophy	2019-05-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000413588	SCV001246248	pathogenic	not provided	2017-10-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413588	SCV001395429	pathogenic	not provided	2024-01-26	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 3719 of the USH2A protein (p.Arg3719His). This variant is present in population databases (rs527236139, gnomAD 0.02%). This missense change has been observed in individual(s) with USH2A-related disease (PMID: 25133613, 28157192, 29641573, 30190494, 30280194). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 143170). 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. For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000678643	SCV001573533	likely pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.11156G>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: PS1, PM2, PP1. Based on this evidence we have classified this variant as Likely Pathogenic.
Genome-Nilou Lab	RCV000132701	SCV001821865	likely pathogenic	Usher syndrome type 2A	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000678643	SCV001821876	likely pathogenic	Retinitis pigmentosa 39	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000413588	SCV002021610	likely pathogenic	not provided	2021-08-06	criteria provided, single submitter	clinical testing
3billion	RCV000132701	SCV002521047	likely pathogenic	Usher syndrome type 2A	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000143170). A different missense change at the same codon (p.Arg3719Leu) has been reported to be associated with USH2A related disorder (PMID: 31998945). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226212	SCV003922469	pathogenic	Usher syndrome	2023-03-01	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.11156G>A (p.Arg3719His) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) 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 5.6e-05 in 251302 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (5.6e-05 vs 0.011), allowing no conclusion about variant significance. c.11156G>A has been reported in the literature in multiple individuals affected with USH2A-related disorders (e.g., Chen_2014, Yang_2015, Gao_2021), and the variant has been shown to segregate with disease in affected family members. These data indicate that the variant is very likely to be associated with disease. 13 ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments. Five submitters classified the variant as pathogenic, 7 submitters classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000678643	SCV004208167	pathogenic	Retinitis pigmentosa 39	2024-03-09	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV001074730	SCV004707868	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000132701	SCV004809714	pathogenic	Usher syndrome type 2A	2024-04-04	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000132701	SCV005051993	pathogenic	Usher syndrome type 2A	2024-02-01	criteria provided, single submitter	curation
Department of Ophthalmology and Visual Sciences Kyoto University	RCV000132701	SCV000172654	probable-pathogenic	Usher syndrome type 2A		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504711	SCV000598766	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678643	SCV000804731	uncertain significance	Retinitis pigmentosa 39	2016-09-01	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000504711	SCV000926712	likely pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Natera, Inc.	RCV000132701	SCV001451992	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732702	SCV005361787	pathogenic	USH2A-related disorder	2024-06-24	no assertion criteria provided	clinical testing	The USH2A c.11156G>A variant is predicted to result in the amino acid substitution p.Arg3719His. This variant has been reported in the homozygous and compound heterozygous state in many individuals with autosomal recessive retinitis pigmentosa and Usher syndrome type (Chen et al. 2014. PubMed ID: 25133613; Table S2, Weisschuh et al. 2020. PubMed ID: 32531858; Table S2, Gao et al. 2021. PubMed ID: 32188678). This variant also segregated with disease in a single family with two affected and two unaffected siblings (Yang et al. 2015. PubMed ID: 26496393). This variant is reported in 0.020% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.