ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.6326C>T (p.Thr2109Ile)

gnomAD frequency: 0.00004  dbSNP: rs377670513
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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 RCV001089684 SCV001245168 likely pathogenic Usher syndrome 2019-11-26 reviewed by expert panel curation The c.6326C>T (p.Thr2109Ile) variant in MYO7A is present in 8/128408 (0.00003% CI 95%) of European alleles in gnomAD (PM2). The variant has been detected in 2 probands with clinical features of Usher syndrome (PP4; SCV000199631.4). At least one proband displayed congenital progressive profound sensorineural hearing loss and retinitis pigmentosa, features of Usher syndrome (PP4; SCV000199631.4). In one proband, a pathogenic or suspected-pathogenic variant was observed in trans (VCV000043313.2). In the other proband, a variant of uncertain significance was observed in trans (VCV000178667.1; SCV000199631.4; PM3). Both probands had affected siblings in whom variants segregated (PP1). The REVEL computational prediction analysis tool produced a score of 0.821, 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 the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2, PM3, PP3, PP1, PP4).
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000151522 SCV000199631 likely pathogenic Rare genetic deafness 2017-07-25 criteria provided, single submitter clinical testing The p.Thr2109Ile variant in MYO7A has been identified by our laboratory in two u nrelated individuals with clinical features of Usher syndrome and segregated in two affected family members. In both families, a second MYO7A variant was identi fied on the remaining copy of the gene. The age of onset of the retinitis pigmen tosa in two siblings was reported to be in the mid to late 30s, which is atypica l for classic type 1 Usher syndrome. The two affected siblings in the other fami ly presented hearing loss but no reported vision findings at the age under 5. Th e p.Thr2109Ile variant has been identified in 8/126680 European chromosomes and 1/24022 African chromosomes by the Genome Aggregation Database (gnomAD, http://g; dbSNP rs377670513); however, its frequency is low enou gh to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that the p.Thr2109Ile variant may impac t the protein. In summary, although additional studies are required to fully est ablish its clinical significance, the p.Thr2109Ile variant is likely pathogenic.
Eurofins NTD LLC (GA) RCV000591925 SCV000705142 uncertain significance not provided 2017-01-09 criteria provided, single submitter clinical testing
Invitae RCV000591925 SCV002148212 pathogenic not provided 2021-09-24 criteria provided, single submitter clinical testing

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