Submissions for variant NM_206933.4(USH2A):c.12574C>T (p.Arg4192Cys)

gnomAD frequency: 0.00004  dbSNP: rs750396156

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001089679	SCV001245163	likely pathogenic	Usher syndrome	2023-11-15	reviewed by expert panel	curation	The c.12574C>T variant in USH2A is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 4192 (p.Arg4192Cys). The highest population minor allele frequency in gnomAD v4.0 is 0.012% (144/1180032 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.599, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant was observed in at least 2 individuals with Usher syndrome and at least 10 individuals with isolated retinitis pigmentosa (RP) who were either homozygous or who carried a second P/LP variant in USH2A (PMID: 24516651, 27460420, 23940504, 27157150, 34906470, 24625443, 28127548, 28041643, 30190494, 29912909, 32176120, 33576794, 34781295, 36785559). At least one of these individuals was clinically evaluated and confirmed to have both sensorineural hearing loss and retinitis pigmentosa, which are highly specific for Usher syndrome (PP4; PMID: 27460420). Of note, an additional proband harbored this variant in cis with the known pathogenic p.Cys759Phe variant (PMID: 29912909), however the VCEP felt that the evidence supporting the pathogenicity of the p.Arg4192Cys variant outweighed this observation. Patients with this variant may present with either autosomal recessive (AR) Usher syndrome or with AR isolated RP. Isolated RP presentations are more common when the variant is seen with missense variants while Usher syndrome is more common when it is found with truncating variants. In summary, the clinical significance of this variant is likely pathogenic based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_VeryStrong, PP4. (ClinGen Hearing Loss VCEP specifications version 2, 11.15.2023)
Eurofins Ntd Llc (ga)	RCV000498898	SCV000332810	uncertain significance	not provided	2015-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000498898	SCV000589528	pathogenic	not provided	2024-05-10	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: 32531858, 34758253, 23940504, 24516651, 27157150, 24625443, 25649381, 28041643, 32176120, 32581362, 34426522, 33576794, 36011334, 34948090, 32637036, 34781295, 30190494, 28127548, 35266249, 36785559, 29912909, 27460420)
Counsyl	RCV000675149	SCV000800749	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-02-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000498898	SCV001207227	pathogenic	not provided	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4192 of the USH2A protein (p.Arg4192Cys). This variant is present in population databases (rs750396156, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive retinitis pigmentosa (arRP) (PMID: 23940504, 27157150, 29912909, 32176120, 33576794). 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: 281818). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075586	SCV001241213	pathogenic	Retinal dystrophy	2019-01-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000498898	SCV001246244	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	USH2A: PM3:Very Strong, PM2, PM5
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000498898	SCV001446632	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000678644	SCV001573664	likely pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.12574C>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: PM2, PM3, PP1, PP4, BP2. Based on this evidence we have classified this variant as Likely Pathogenic.
Genomics England Pilot Project, Genomics England	RCV000678644	SCV001760009	likely pathogenic	Retinitis pigmentosa 39		criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000504963	SCV001950407	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Arg4192Cys 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: PM2, PM3, PP1, PP4, BP2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	RCV001089679	SCV003927135	likely pathogenic	Usher syndrome	2022-12-31	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001089679	SCV003934272	pathogenic	Usher syndrome	2023-05-19	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.12574C>T (p.Arg4192Cys) results in a non-conservative amino acid change located in the fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249476 control chromosomes (gnomAD). c.12574C>T has been reported in the literature as a biallelic genotype in at least two individuals affected with Usher Syndrome and multiple individuals affected with retinitis pigmentosa, including at least one family where it segregated with disease (e.g.Corton_2013, Coppieters_2014, de Castro-Miro_2014, 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. However, another variant affecting the same amino acid (p.R4192H) has also been classified as pathogenic by our laboratory, suggesting Arg4192 may be important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 27460420, 24625443, 23940504, 24516651). Thirteen submitters, including an expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=5)/likely pathogenic (n=6) or VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000678644	SCV004208253	pathogenic	Retinitis pigmentosa 39	2024-03-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075586	SCV005069824	likely pathogenic	Retinal dystrophy	2021-01-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786650	SCV005398875	likely pathogenic	Usher syndrome type 2A	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Usher syndrome, type 2A (MIM#276901) and retinitis pigmentosa (RP; MIM# 6138093). Null variants are associated with Usher syndrome while homozygous missense which lead to partially functional proteins typically causes non-syndromic RP (PMID: 20301515). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v4: 149 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4: 500 heterozygotes, 1 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by an expert panel (ClinVar). Specifically, it has been observed compound heterozygous with c.11874_11875delCA in a 17 year old individual with night blindness, mild peripheral field constriction, and hearing impairment (PMID: 36011334). In addition, it has been observed in compound heterozygous with p.(Cys795Phe) in an 18 year old individual diagnosed with simplex retinitis pigmentosa (PMID: 30190494). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000675149	SCV005638672	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2024-06-07	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504963	SCV000598776	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678644	SCV000804733	likely pathogenic	Retinitis pigmentosa 39	2016-09-01	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000504963	SCV000926913	likely pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000498898	SCV001921192	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000498898	SCV001954205	likely pathogenic	not provided		no assertion criteria provided	clinical testing