ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.1817G>A (p.Arg606His) (rs782311929)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel, RCV000710344 SCV000840541 uncertain significance Nonsyndromic hearing loss and deafness 2018-09-28 reviewed by expert panel curation The allele frequency of the p.Arg505His variant in MYO7A is 0.035% (8/23150) South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). This variant has been detected in 1 patient with hearing loss in trans with pathogenic or suspected-pathogenic variants (PM3; Partners LMM internal data SCV000731600.1). Computational prediction tools and conservation analysis suggest that the p.Arg606His variant may impact the protein (PP3). One patient with a variant in this gene displayed features of sensorineural hearing loss and delayed walking (PP4; Partners LMM internal data SCV000731600.1). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_P, PM3, PP3, PP4.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000613132 SCV000731600 uncertain significance not specified 2017-07-27 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg606His variant in MYO7A has been reported in 1 individual with Usher syndrome type I; however, this individual also harbored a homozygous CDH23 variant that likely ex plained the disease (Le Quesne Stabej et al. 2012; LOVD https://grenada.lumc.nl/ LOVD2/Usher_montpellier). It has been reported by our laboratory in 1 individual with hearing loss and delayed walking who had a second pathogenic variant on th e other copy of MYO7A. This variant has been identified in 2/14988 European chr omosomes and 1/1622 East Asian chromosomes by the Genome Aggregation Database (g nomAD, http://gnomad.broadinstitute.org; dbSNP rs782311929); however, this frequ ency 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. I n summary, while there is some suspicion for a pathogenic role, the clinical sig nificance of this variant is uncertain.

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