Submissions for variant NM_206933.4(USH2A):c.1055C>T (p.Thr352Ile)

gnomAD frequency: 0.00001  dbSNP: rs780308389

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824796	SCV000709742	pathogenic	Rare genetic deafness	2017-04-11	criteria provided, single submitter	clinical testing	The p.Thr352Ile variant in USH2A has been reported in at least 7 individuals wit h Usher syndrome, 5 of whom carried a second pathogenic variant on the other all ele (Baux 2007, Cremers 2007, Dreyer 2008, Bonnet 2011, Besnard 2013, Lenarduzzi 2015, Bonnet 2016). This variant has also been identified in 2/111896 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org; dbSNP rs780308389). This frequency in the general population is low en ough to be consistent with a recessive carrier frequency for Usher syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosoma l recessive Usher syndrome based on multiple occurrences with a second pathogeni c variant in affected individuals.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804683	SCV000944603	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 352 of the USH2A protein (p.Thr352Ile). This variant is present in population databases (rs780308389, gnomAD 0.002%). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 17405132, 24498627, 25575603, 28653555, 29142287). 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: 438002). 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%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075415	SCV001241038	pathogenic	Retinal dystrophy	2018-08-06	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000665487	SCV001573413	likely pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.1055C>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, PP3, PM1-S. Based on this evidence we have classified this variant as Likely Pathogenic.
DASA	RCV001836644	SCV002097282	pathogenic	USH2A-related disorder	2022-02-14	criteria provided, single submitter	clinical testing	The c.1055C>T;p.(Thr352Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 438002; PMID: 29142287; 28653555; 27460420; 25575603; 24498627; 21569298; 18273898; 17405132) - PS4. The variant is present at low allele frequencies population databases (rs780308389 - gnomAD 0.00007968%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Thr352Ile) was detected in trans with a pathogenic variant (PMID: 29142287; 28653555; 25575603; 24498627; 17405132) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 29142287) - PP1_moderate. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Genome-Nilou Lab	RCV000665487	SCV004182913	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001834622	SCV004182914	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000804683	SCV005201532	pathogenic	not provided	2023-09-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 33411470, 28653555, 31589614, 33576794, 35266249, 29142287, 17405132, 24498627, 25575603, 16963483, 18273898, 27460420, 34781295, 34948090, 28041643, 21569298)
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504656	SCV000598763	likely pathogenic	Usher syndrome	2015-01-01	no assertion criteria provided	research
Counsyl	RCV000665487	SCV000789617	likely pathogenic	Retinitis pigmentosa 39	2017-02-14	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001834622	SCV002094002	pathogenic	Usher syndrome type 2A	2021-04-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001836644	SCV004710665	likely pathogenic	USH2A-related disorder	2024-01-16	no assertion criteria provided	clinical testing	The USH2A c.1055C>T variant is predicted to result in the amino acid substitution p.Thr352Ile. This variant was reported in the compound heterozygous or homozygous states in individuals with retinitis pigmentosa or Usher syndrome (Magliulo et al. 2017. PubMed ID: 28653555; Table S4 & S5, Colombo et al. 2021. PubMed ID: 33576794; Colombo et al. 2021. PubMed ID: 34781295; Table S2, Mansard et al. 2021. PubMed ID: 34948090; Table S1, Karali et al. 2022. PubMed ID: 36460718). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is listed in ClinVar as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/438002/). This variant is interpreted as likely pathogenic.