Submissions for variant NM_206933.4(USH2A):c.12575G>A (p.Arg4192His)

gnomAD frequency: 0.00046  dbSNP: rs199605265

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152569	SCV000201820	uncertain significance	not specified	2014-07-16	criteria provided, single submitter	clinical testing	The Arg4192His variant in USH2A has been reported in four individuals with autosomal recessive retinitis pigmentosa (McGee 2010, Avila-Fernandez 2010, Tucker 2013). Three of these individuals were homozygous or compound heterozygous, and one was only reported to be heterozygous for this variant but there was no information about a second variant. The Arg4192His variant has been identified in 0.023% (2/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs199605265). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The arginine (Arg) at position 4192 is not conserved in mammals or evolutionary distant species, including many species carrying a histidine (His) at this position, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest that the Arg4192His variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the Arg4192His variant is uncertain, these data suggest that is more likely to be benign.
Eurofins Ntd Llc (ga)	RCV000480057	SCV000331629	pathogenic	not provided	2015-05-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000480057	SCV000565653	pathogenic	not provided	2024-02-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32531858, 32637036, 25649381, 23591405, 26427457, 28131284, 26880948, 28559085, 21151602, 22334370, 27596865, 28118666, 30217765, 32326409, 31980526, 32036094, 32581362, 26806561, 25412400, 28041643, 26927203, 29276052, 31049658, 31736247, 32269941, 31456290, 28805479, 27160483, 20507924, 22135276, 34327195, 32675063, 28894305, 33576794, 32037395, 23991284, 34961661, 34781295, 35266249)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000480057	SCV001057184	pathogenic	not provided	2024-01-31	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 4192 of the USH2A protein (p.Arg4192His). This variant is present in population databases (rs199605265, gnomAD 0.9%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with mild or late onset deafness and/or nonsyndromic retinal disease (PMID: 21151602, 22135276, 22334370, 23991284, 25649381, 28118666, 28559085, 28894305; Invitae). 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: 166434). 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%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074420	SCV001240002	pathogenic	Retinal dystrophy	2019-08-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000480057	SCV001246243	uncertain significance	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000480057	SCV001447609	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000675140	SCV001520107	pathogenic	Retinitis pigmentosa 39	2019-02-08	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000675140	SCV001573312	pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.12575G>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, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000505125	SCV001950420	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Arg4192His variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Revvity Omics, Revvity	RCV000480057	SCV003828074	uncertain significance	not provided	2019-06-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226215	SCV003922470	pathogenic	Usher syndrome	2023-03-23	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.12575G>A (p.Arg4192His) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 280866 control chromosomes in the gnomAD database, including one homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00057 vs 0.011), allowing no conclusion about variant significance. c.12575G>A has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with retinitis pigmentosa or hereditary retinal disorders (Avila-Fernandez_2010, Martin-Merida_2019, Weisschuh_2020, Ganapathi_2022) and this variant co-segregated with the disease (Avila-Fernandez_2010, Martin-Merida_2019). 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. 15 submitters (evaluation after 2014) cite this variant as uncertain significance (n=5), likely pathogenic (n=2) and pathogenic (n=8). Based on the evidence outlined above, the variant was classified as pathogenic.
3billion	RCV001004143	SCV004013681	pathogenic	Usher syndrome type 2A		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: 0.057%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.12; 3Cnet: 0.66). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000166434 / 3billion dataset). A different missense change at the same codon (p.Arg4192Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000281818 / PMID: 23940504). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences	RCV004532711	SCV004119222	pathogenic	USH2A-related disorder	2023-08-02	criteria provided, single submitter	clinical testing	The USH2A c.12575G>A variant is predicted to result in the amino acid substitution p.Arg4192His. This variant has been reported in the compound heterozygous state as causative for retinitis pigmentosa (RP) and Usher syndrome type 2 (Lenassi et al. 2015. PubMed ID: 25649381; Neveling et al. 2012. PubMed ID: 22334370; Avila-Fernandez et al. 2010. PubMed ID: 21151602). At PreventionGenetics, we have seen this variant either in the homozygous state or along with a second causative variant in several unrelated patients (internal data). This variant is reported in 0.89% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygote (http://gnomad.broadinstitute.org/variant/1-215848678-C-T), which is relatively common for disease causing variant. The majority of submitters to ClinVar interpret this variant as pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/166434/). Given the evidence, we interpret c.12575G>A (p.Arg4192His) as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001004143	SCV004812146	likely pathogenic	Usher syndrome type 2A	2022-06-22	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PM5,BP4
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001004143	SCV005051994	likely pathogenic	Usher syndrome type 2A	2024-02-01	criteria provided, single submitter	curation
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505125	SCV000598777	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Counsyl	RCV000675140	SCV000800729	uncertain significance	Retinitis pigmentosa 39	2019-05-07	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000505125	SCV000926717	uncertain significance	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000505125	SCV001161337	pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
Baylor Genetics	RCV001004143	SCV001162876	uncertain significance	Usher syndrome type 2A	2022-01-26	no assertion criteria provided	clinical testing