ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.13316C>T (p.Thr4439Ile) (rs753330544)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724329 SCV000231908 pathogenic not provided 2014-11-17 criteria provided, single submitter clinical testing
Counsyl RCV000666708 SCV000791051 pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-04-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000666708 SCV000893283 pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000724329 SCV000935692 pathogenic not provided 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 4439 of the USH2A protein (p.Thr4439Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another USH2A variant in individuals affected with Usher syndrome (PMID: 25521520, 28041643, 22135276, 27460420, 26416264, 27957503, 24944099). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 198344). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074360 SCV001239936 pathogenic Retinal dystrophy 2019-07-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000724329 SCV001246241 pathogenic not provided 2020-11-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001449693 SCV001652945 likely pathogenic Usher syndrome 2020-06-19 criteria provided, single submitter clinical testing The p.Thr4439Ile variant in USH2A has been reported in 5 European individuals with Usher syndrome type 2, four of whom were compound heterozygous for a second likely pathogenic USH2A variant (Bonnet 2016 PMID:27460420, Dreyer 2008 PMID:18273898, Le Quesne Stabej 2012 PMID:22135276). It has also been identified in 0.003% (3/113178) of European chromosomes by gnomAD ( However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID 198344) as pathogenic/likely pathogenic on 11/26/2018. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PM3 , PM2, PP3, PP4.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504835 SCV000598784 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000179630 SCV000804734 likely pathogenic Usher syndrome, type 2A 2016-09-01 no assertion criteria provided clinical testing
GeneDx RCV000724329 SCV001793789 pathogenic not provided 2020-12-23 no assertion criteria provided clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32581362, 24944099, 25521520, 28559085, 27460420, 28041643, 28944237, 22135276, 20440071, 26927203, 18273898)

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