ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.2904G>T (p.Glu968Asp) (rs111033233)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036100 SCV000059752 pathogenic Rare genetic deafness 2018-05-15 criteria provided, single submitter clinical testing The p.Glu968Asp variant in MYO7A has been identified at least 7 individuals with clinical features of Usher syndrome, including 1 homozygote and 5 compound hete rozygotes (Bharadwaj 2000, Ouyang 2005, Jacobson 2008, Le Quesne 2012, Bujakowsk a 2014, Zhao 2015, Sloan-Heggen 2016, Bonnet 2016, LMM unpublished data). This v ariant has been identified in 4/125720 European chromosomes by the Genome Aggreg ation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033233). Al though this variant has been seen in the general population, its frequency is lo w enough to be consistent with a recessive carrier frequency. The p.Glu968Asp va riant is located in the last base of the exon, which is part of the 5? splice re gion and computational tools predict altered splicing. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner based upon proband counts, frequency in controls, and predicte d impact on protein. ACMG/AMP Criteria applied: PM3_VeryStrong, PS4, PM2, PVS1_M oderate.
GeneDx RCV000414534 SCV000490657 pathogenic not provided 2015-09-22 criteria provided, single submitter clinical testing The E968D missense variant in the MYO7A gene has been reported in association with Usher syndrome type I (Bharadwaj et al., 2000; Jacobson et al., 2009). In both reports, E968D was identified in a patient who also harbored a second missense variant. The c.2904 G>T pathogenic variant changes the last nucleotide in exon 23 of the MYO7A gene, which might affect the donor splice site and result in exons skipping. Splice prediction algorithms indicate that the E968D variant destroys the donor splice site. E968D was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret E968D to be a pathogenic variant.

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