ClinVar Miner

Submissions for variant NM_004999.4(MYO6):c.3610C>T (p.Arg1204Trp)

dbSNP: rs876657911
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000218835 SCV000272143 uncertain significance not specified 2015-02-04 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg1204Tr p variant in MYO6 has been reported in 1 Dutch individual with hearing loss and segregated with disease in 9 affected family members (Oonk 2013). However, thre e unaffected individuals under or around the reported mean age of onset (38 yrs) also carried the variant, and the proband in this family had a different phenot ype than the other 9 affected family members with a much earlier age of onset an d more severe hearing impairment. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that t he Arg1204Trp variant may impact the protein, though this information is not pre dictive enough to determine pathogenicity. In summary, while there is some suspi cion for a pathogenic role, the clinical significance of this variant is uncerta in due to inconsistencies in the segregation and age of onset reported for the D utch family described above.
GeneDx RCV001753647 SCV001986294 likely pathogenic not provided 2024-10-28 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18348273, 18212818, 23635807, 12687499, 24123792, 28000701, 33710140, 23340379, 38400873, 35661827, 39019031)
Labcorp Genetics (formerly Invitae), Labcorp RCV001753647 SCV005834749 pathogenic not provided 2024-07-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1204 of the MYO6 protein (p.Arg1204Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with deafness (PMID: 23340379, 33710140). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228996). 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 MYO6 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

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