ClinVar Miner

Submissions for variant NM_016239.3(MYO15A):c.8050T>C (p.Tyr2684His) (rs376351191)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000418317 SCV000513828 likely pathogenic not provided 2018-08-15 criteria provided, single submitter clinical testing The Y2684H variant in the MYO15A gene has been observed in trans with another MYO15A variant in a patient with congenital bilateral non-syndromic sensorineural deafness (Cabanillas et al., 2018) and in a patient with hearing loss previously referred for clinical exome sequencing at GeneDx (Retterer et al., 2016). The Y2684H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Y2684H 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-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret Y2684H as a likely pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000353974 SCV000401190 uncertain significance Nonsyndromic Hearing Loss, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000607828 SCV000711137 uncertain significance not specified 2017-01-13 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr2684His variant in MYO15A has been previously reported in an individual with hearing loss and segregated in an affected sibling (Santos Serrao de Castro, 2012). This variant was identified in 6/65774 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs376351191). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. 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, while there is some suspicion for a pathogenic role, the clinical significance of the p.Tyr2684His variant is uncertain.

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