Submissions for variant NM_206933.4(USH2A):c.13274C>T (p.Thr4425Met)

gnomAD frequency: 0.00004  dbSNP: rs201238640

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001358731	SCV001554576	pathogenic	Usher syndrome	2024-11-22	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.13274C>T (p.Thr4425Met) results in a non-conservative amino acid change located in a Fibronectin type III repeat 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 4.4e-05 in 250930 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum for a pathogenic variant in USH2A causing Usher Syndrome (0.011), allowing no conclusion about variant significance. c.13274C>T has been reported in the literature in multiple compound heterozygous individuals affected with Usher Syndrome and Retinitis Pigmentosa (e.g. van Wijk_2004, Baux_2007, Neverling_2012, van Huet_2015, Bonnet_2016, Toms_2020, Gao_2021, Mansard_2021). These data indicate that the variant is very likely to be associated with disease. In some of these cases, the variant was reported in complex alleles with p.Arg4115Cys (e.g. van Wijk_2004, Bonnet_2016) and/or p.Cys759Phe (e.g. Baux_2007, Mansard_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17405132, 24944099, 27460420, 32188678, 22334370, 26927203, 31998945, 32581362, 25999674, 15015129, 34948090). ClinVar contains an entry for this variant (Variation ID: 438011). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000733677	SCV002237273	pathogenic	not provided	2024-06-08	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 4425 of the USH2A protein (p.Thr4425Met). This variant is present in population databases (rs201238640, gnomAD 0.008%). This missense change has been observed in individuals with USH2A-related conditions (PMID: 24944099, 31266775, 32188678, 32581362). ClinVar contains an entry for this variant (Variation ID: 438011). 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 expected to disrupt USH2A protein function with a positive predictive value of 95%. This variant disrupts the p.Thr4425 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 30718709), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003470634	SCV004208258	likely pathogenic	Retinitis pigmentosa 39	2024-02-19	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004817730	SCV005071041	likely pathogenic	Retinal dystrophy	2019-01-01	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504678	SCV000598783	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Eurofins Ntd Llc (ga)	RCV000733677	SCV000861770	uncertain significance	not provided	2018-06-28	flagged submission	clinical testing
Clinical Genetics, Academic Medical Center	RCV000733677	SCV001922776	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000733677	SCV001953944	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000733677	SCV001966426	pathogenic	not provided		no assertion criteria provided	clinical testing