Submissions for variant NM_206933.4(USH2A):c.10342G>A (p.Glu3448Lys)

gnomAD frequency: 0.00008  dbSNP: rs368049814

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000191142	SCV000245551	pathogenic	Retinitis pigmentosa 39	2024-03-27	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000484923	SCV000339979	likely pathogenic	not provided	2016-04-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000484923	SCV000565649	likely pathogenic	not provided	2024-05-10	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31429209, 24265693, 26667666, 28041643, 25412400, 20507924, 27160483, 32188678, 24901346, 32037395, 36011334, 35266249, 32675063, 24603341, 28761320, 36819107, 36672815, 37217489, 28981474, 32176120)
Counsyl	RCV000675180	SCV000800809	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2018-04-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000484923	SCV001147669	likely pathogenic	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV001002723	SCV001156416	pathogenic	Usher syndrome type 2A	2019-02-01	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001073310	SCV001238848	pathogenic	Retinal dystrophy	2018-11-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000484923	SCV001403149	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3448 of the USH2A protein (p.Glu3448Lys). This variant is present in population databases (rs368049814, gnomAD 0.008%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 24265693, 26667666, 28761320, 28981474). 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: 209203). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000191142	SCV001573612	likely pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.10342G>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, PP3. Based on this evidence we have classified this variant as Likely Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000484923	SCV001905660	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804928	SCV002050746	pathogenic	Usher syndrome	2021-12-03	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.10342G>A (p.Glu3448Lys) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251302 control chromosomes (gnomAD). c.10342G>A has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Retinitis Pigmentosa and Usher Syndrome (example: McGee_2011, Eisenberger_2013, Iglesias_2014, Maranhao_2014, Comander_2017, Jones_2017, Gao_2021). 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. Eleven ClinVar submitters have assessed the variant since 2014: seven have classified it as likely pathogenic and four as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001002723	SCV002583282	pathogenic	Usher syndrome type 2A		criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000191142	SCV002761820	likely pathogenic	Retinitis pigmentosa 39	2021-04-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000484923	SCV003814214	likely pathogenic	not provided	2022-08-30	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504830	SCV000598761	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Natera, Inc.	RCV001002723	SCV001457064	likely pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing