ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.4106C>T (p.Ser1369Leu) (rs201709513)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041837 SCV000065533 uncertain significance not specified 2016-10-25 criteria provided, single submitter clinical testing The p.Ser1369Leu variant in USH2A has been previously reported in three individu als with Usher syndrome, one individual with retinitis pigmentosa, and one indiv idual with hearing loss (Colombo 2015, Cremers 2007, Dad 2015, Wang 2014, LMM da ta). In the proband with retinitis pigmentosa, a second variant of uncertain si gnificance was identified and the two variants segregated in an affected sibling ; however, cis/trans testing was not performed (Wang 2014). In the remaining pr obands, a pathogenic variant affecting the remaining copy of USH2A was not ident ified. This variant has been identified in 13/65610 European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs201 709513); however, this frequency is not high enough to rule out a pathogenic rol e. The serine (Ser) at position 1369 is not conserved through species, with 2 m ammals (squirrel and brush-tailed rat) and 2 bird species having a leucine, sugg esting that this change may be tolerated. Additional computational prediction t ools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ser1369Leu variant is uncertain.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726718 SCV000702404 uncertain significance not provided 2016-11-08 criteria provided, single submitter clinical testing
Counsyl RCV000665274 SCV000789366 uncertain significance Usher syndrome, type 2A; Retinitis pigmentosa 39 2017-01-26 criteria provided, single submitter clinical testing
Invitae RCV000726718 SCV001234991 likely pathogenic not provided 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1369 of the USH2A protein (p.Ser1369Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs201709513, ExAC 0.02%). This variant has been observed in individual(s) with USH2A-related disease (PMID: 27957503, 24154662, 26927203, 20591486, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48511). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Blueprint Genetics RCV001074345 SCV001239920 likely pathogenic Retinal dystrophy 2019-07-16 criteria provided, single submitter clinical testing

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