Submissions for variant NM_206933.4(USH2A):c.653T>A (p.Val218Glu)

gnomAD frequency: 0.00001  dbSNP: rs397518026

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041890	SCV000065586	pathogenic	Rare genetic deafness	2016-08-09	criteria provided, single submitter	clinical testing	The p.Val218Glu variant in USH2A has been reported in at least 8 individuals wit h Usher syndrome, all of whom carried a second, pathogenic USH2A variant on the other allele (Leroy 2001, Cremers 2007, Baux 2007, Herrera 2008, Bonnet 2011, Gl ockle 2013, Besnard 2014). This variant has also been identified in 5/66590 Euro pean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org; dbSNP rs397518026). Although it has been seen in the general populat ion, its frequency is low enough to be consistent with a recessive carrier frequ ency. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner based upon its occurrence in tr ans with known pathogenic USH2A variants in multiple affected individuals.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000408647	SCV000963510	pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 218 of the USH2A protein (p.Val218Glu). This variant is present in population databases (rs397518026, gnomAD 0.007%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 11311042, 16963483, 21569298, 28559085). 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: 48564). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075204	SCV001240818	pathogenic	Retinal dystrophy	2018-11-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000408647	SCV001250066	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	USH2A: PM3:Very Strong, PM2, PP4
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000408647	SCV001447913	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000504825	SCV001950401	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Val218Glu 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, PP3, PM3-S. 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.
GeneDx	RCV000408647	SCV002577255	pathogenic	not provided	2022-09-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17405132, 18463160, 20052763, 16963483, 32531858, 11311042, 28944237, 27460420, 23591405, 21569298, 18281613, 27318125, 25902111, 26654877, 24498627, 28041643, 28559085, 24944099)
MGZ Medical Genetics Center	RCV001826599	SCV002579878	pathogenic	Usher syndrome type 2A	2022-05-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000675152	SCV004207693	pathogenic	Retinitis pigmentosa 39	2023-12-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075204	SCV005071792	likely pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000408647	SCV000484497	uncertain significance	not provided	2015-09-24	flagged submission	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504825	SCV000598821	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Counsyl	RCV000675152	SCV000800758	pathogenic	Retinitis pigmentosa 39	2017-04-20	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000408647	SCV001923955	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000408647	SCV001959678	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826599	SCV002094022	pathogenic	Usher syndrome type 2A	2021-09-29	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537156	SCV004720609	pathogenic	USH2A-related disorder	2024-09-05	no assertion criteria provided	clinical testing	The USH2A c.653T>A variant is predicted to result in the amino acid substitution p.Val218Glu. This variant has been reported in the compound heterozygous state with a second pathogenic or likely pathogenic USH2A variant in multiple unrelated affected patients (Leroy et al. 2001. PubMed ID: 11311042; Baux et al. 2007. PubMed ID: 17405132; Cremers et al. 2007. PubMed ID: 16963483; Herrera et al. 2008. PubMed ID: 18281613; Besnard et al. 2014. PubMed ID: 24498627; Table S2, Bonnet et al. 2016. PubMed ID: 27460420; Table S2, Carss et al. 2016. PubMed ID: 28041643). This variant is reported in 0.0071% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.