ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.2002C>T (p.Arg668Cys) (rs397516292)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000675142 SCV000800732 uncertain significance Deafness, autosomal recessive 2; Usher syndrome, type 1 2017-09-06 criteria provided, single submitter clinical testing
GeneDx RCV000489211 SCV000577639 uncertain significance not provided 2018-02-16 criteria provided, single submitter clinical testing The R668C variant in the MYO7A gene has been reported previously in a single patient with Usher syndrome type IB who also had another variant in the MYO7A gene (Sloan-Heggen et al., 2016). The R668C variant is observed in 2/244686 (0.008%) alleles in large population cohorts (Lek et al., 2016). The R668C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A different missense variant at the same residue (R668H) was identified in multiple members from a single family with autosomal dominant non-syndromic sensorineural hearing loss (Sang et al., 2013), supporting the functional importance of this residue of the protein. We interpret R668C as a variant of uncertain significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036072 SCV000059724 uncertain significance not specified 2012-04-11 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Arg668Cys v ariant in MYO7A has not been reported in the literature nor previously identifie d by our laboratory. Computational analyses (biochemical amino acid properties, conservation, SIFT, PolyPhen2) suggest that the Arg668Cys variant may impact the protein, though this information is not predictive enough to determine pathogen icity. If the Arg668Cys variant is found to be in trans (on separate copies of t he gene) with the Tyr333X variant, then the presence of the Arg668Cys variant in combination with a pathogenic variant in a patient with hearing loss increases the likelihood that the Arg668Cys variant is pathogenic. In summary, the clinica l significance of this variant cannot be determined with certainty; however base d upon the arguments described above, and if the Arg668Cys variant is shown to b e in trans, we would lean towards a more likely pathogenic role for this variant .

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