ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.6560G>A (p.Gly2187Asp) (rs397516332)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000036241 SCV001245160 likely pathogenic Usher syndrome 2019-11-26 reviewed by expert panel curation The allele frequency of the p.Gly2187Asp variant in the MYO7A gene is 0.001% (1//84018) of non-Finnish European chromosomes by gnomAD, which is a low enough frequency to apply PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). This variant has been observed presumed in trans with a pathogenic variant in one individual with Usher syndrome type 1, and confirmed in trans with a different pathogenic variant in another in patient with hearing loss and vestibular dysfunction (PM3; PMID: 10930322; Partners LMM internal data RCV000036241.3). One of these patients with the variant in this gene also displayed features consistent with Usher syndrome, a condition highly specific for MYO7A (PP4; PMID: 10930322). The REVEL computational prediction analysis tool produced a score of 0.915, which is above the threshold necessary to apply PP3. Functional evidence suggests this variant may disrupt necessary protein-protein interactions between MYO7A and USH1C; however PS3 will not be applied as this assay did not meet criteria specified by the ClinGen Hearing Loss Expert Panel (PMID: 28439001). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2, PM3, PP4, PP3).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036241 SCV000059893 likely pathogenic Usher syndrome 2019-03-13 criteria provided, single submitter clinical testing The p.Gly2187Asp variant in MYO7A has been reported in 1 individual with Usher syndrome (Bharadwaj 2000) and identified by our laboratory in 1 individual with profound congenital hearing loss and vestibular problems. Both individuals were compound heterozygous for a second pathogenic or likely pathogenic MYO7A variant. This variant has been identified in 0.001% (1/84018) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397516332). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that the p.Gly2187Asp variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly2187Asp variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_Strong, PM2, PP3
Counsyl RCV000675126 SCV000800695 uncertain significance Deafness, autosomal recessive 2; Usher syndrome type 1 2018-04-13 criteria provided, single submitter clinical testing

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