ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 .
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.
Counsyl RCV000675142 SCV000800732 uncertain significance Deafness, autosomal recessive 2; Usher syndrome type 1 2017-09-06 criteria provided, single submitter clinical testing
Invitae RCV000489211 SCV001397007 likely pathogenic not provided 2019-10-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 668 of the MYO7A protein (p.Arg668Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs397516292, ExAC 0.01%). This variant has been observed in individual(s) with Usher syndrome (PMID: 26969326, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 43168). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg668 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26969326). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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