ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.1208A>G (p.Tyr403Cys) (rs797044511)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001089675 SCV001245158 likely pathogenic Usher syndrome 2019-11-26 reviewed by expert panel curation The c.1208A>G (p.Tyr403Cys) variant in MYO7A is present in 0.0064% (1/15398) of non-Finnish European alleles in gnomAD (PM2). This variant has been identified in trans with a second suspected-pathogenic variant (VCV000164724.1) in one proband with profound hearing loss and retinitis pigmentosa, clinical features of Usher syndrome (PM3; PP4; SCV000205114.4). The variant also segregated in one affected family member (PP1; SCV000205114.4). The REVEL computational prediction analysis tool produced a score of 0.941, 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, PP3, PM3, PP4).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000155424 SCV000205114 likely pathogenic Rare genetic deafness 2013-06-12 criteria provided, single submitter clinical testing The Tyr403Cys in MYO7A has been identified in two siblings with clinical feature s of Usher syndrome by our laboratory. Both siblings carried a second MYO7A vari ant on the other MYO7A allele. In addition, computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest tha t the Tyr403Cys variant may impact the protein. In summary, this variant is like ly to be pathogenic, though additional studies are required to fully establish i ts clinical significance.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000594093 SCV000705143 uncertain significance not provided 2017-01-09 criteria provided, single submitter clinical testing
Counsyl RCV000675112 SCV000800663 uncertain significance Deafness, autosomal recessive 2; Usher syndrome type 1 2018-02-20 criteria provided, single submitter clinical testing
Invitae RCV000594093 SCV001555376 uncertain significance not provided 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 403 of the MYO7A protein (p.Tyr403Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYO7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 178667). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYO7A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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