ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.10073G>A (p.Cys3358Tyr) (rs148660051)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000515419 SCV000678128 likely pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2016-12-16 criteria provided, single submitter clinical testing C3358Y is primarily associated with retinitis pigmentosa.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000190637 SCV000536900 likely pathogenic Usher syndrome, type 2A 2016-07-19 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000482080 SCV000231295 pathogenic not provided 2017-04-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515419 SCV000611246 likely pathogenic Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000482080 SCV000565648 pathogenic not provided 2018-11-02 criteria provided, single submitter clinical testing The C3358Y variant in the USH2A gene has been reported previously in association with non-syndromic retinitis pigmentosa. Affected individuals were heterozygous for the C3358Y variant in addition to harboring a second variant in the USH2A gene (Avila-Fernandez et al., 2010; Neveling et al., 2012; Le Quesne Stabej et al., 2012; Zhao et al., 2015; Lenassi et al., 2015). The C3358Y variant is observed in 94/126,370 (0.0744%) alleles from individuals of non-Finnish European background in large population cohorts, with no homozygous control individuals reported (Lek et al., 2016). The C3358Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. We interpret C3358Y as a pathogenic variant.
Invitae RCV000482080 SCV000952339 likely pathogenic not provided 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 3358 of the USH2A protein (p.Cys3358Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs148660051, ExAC 0.05%). This variant has been observed on the opposite chromosome (in trans) from a likely pathogenic variant in an individual affected with Usher syndrome (PMID: 22004887) and in combination with other USH2A variants in multiple other individuals affected with retinitis pigmentosa or Usher syndrome with late onset deafness (PMID: 25097241, 25472526, 22135276, 25649381, 22334370). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 197932). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000190637 SCV000538073 likely pathogenic Usher syndrome, type 2A 2016-01-27 criteria provided, single submitter clinical testing The c.10073G>A (p.Cys3358Tyr) missense variant in the USH2A gene has been previously reported in several individuals affected with Usher Syndrome or Retinitis Pigmentosa. This allele was observed in 13 cases out of 914 affected alleles (Lenassi et al., 2015) and is significantly higher than the allele frequency in the ExAC database (13/121292). This variant is often seen in trans with other pathogenic variants (Garcia-Garcia et al., 2011; Le Quesne Stabej et al., 2012; Neveling et al., 2012; Lenassi et al., 2015). This c.10073G>A allele has been reported at low frequency, or is absent in other population databases (Exome Sequencing Project [ESP] = 0.058%, 1000 Genomes = NA). Multiple in silico algorithms predict this variant to have a deleterious effect GERP = 5.76; CADD = 22.4; PolyPhen = 1; SIFT = 0). Reputable diagnostic laboratories have reported this variant as either Likely Pathogenic or Pathogenic for either, Retinitis Pigmentosa or Usher Syndrome, Type 2A. Therefore, this collective evidence supports the classification of the c.10073G>A (p.Cys3358Tyr) as a recessive Likely Pathogenic variant for Usher syndrome, type IIA.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824784 SCV000245680 pathogenic Rare genetic deafness 2016-01-27 criteria provided, single submitter clinical testing The p.Cys3358Tyr variant in USH2A has been reported in over 10 individuals with retinitis pigmentosa, with at least five of these individuals being compound het erozygous for a pathogenic variant on the remaining copy of USH2A (Garcia-Garcia 2011, LeQuesne Stabej 2012, Lenassi 2015, McGee 2010, Neveling 2012, van Huet 2 015, Wang 2014, Zhao 2015, Avila-Fernandez 2010). Two of these individuals were reported to have features of atypical type 2 Usher syndrome, with a later onset hearing loss (Garcia-Garcia 2011, Lenassi 2015). The variant has been identifie d in 33/66704 European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs148660051); however its frequency is low e nough to be consistent with a recessive carrier frequency. Computational predict ion tools and conservation analysis suggest an impact to the protein. In summary , this variant meets our criteria to be classified as pathogenic for autosomal r ecessive retinitis pigmentosa and/or atypical type 2 Usher syndrome, based on th e previously reported individuals.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505000 SCV000598759 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research
SIB Swiss Institute of Bioinformatics RCV000179099 SCV000803576 likely pathogenic Retinitis pigmentosa 39 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Retinitis pigmentosa 39, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3-Strong => PM3 upgraded in strength to Strong (PMID:22334370) (PMID:25649381).

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