ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.631A>G (p.Ser211Gly) (rs111033486)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000036230 SCV001334329 likely pathogenic Usher syndrome 2020-05-06 reviewed by expert panel curation The c.631A>G (p.Ser211Gly) variant in MYO7A was present in 0.009% (6/64570) of non-Finnish European chromosomes in gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been observed in at least 3 probands with Usher syndrome who carried other pathogenic or likely pathogenic variants in MYO7A; in two cases the other variant was confirmed to be in trans (PM3_Strong; PMID: 25472526; Laboratory for Molecular Medicine internal data, SCV000059882.6). All three of these probands displayed hearing loss and retinitis pigmentosa, features highly specific for MYO7A and Usher syndrome (PP4). The REVEL computational prediction analysis tool produced a score of 0.96, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2_Supporting, PM3_Strong, PP3, PP4).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036230 SCV000059882 likely pathogenic Usher syndrome 2019-03-13 criteria provided, single submitter clinical testing The p.Ser211Gly variant in MYO7A has been reported in 3 individuals with clinical features of Usher syndrome (Zhao 2015; LMM internal data). It has also been identified in 0.005% (7/128370) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; rs111033486). 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 this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PM3_Strong, PM2, PP3, PP4
Counsyl RCV000675104 SCV000800647 uncertain significance Deafness, autosomal recessive 2; Usher syndrome type 1 2018-01-02 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001073506 SCV001239049 pathogenic Retinal dystrophy 2019-04-08 criteria provided, single submitter clinical testing

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