ClinVar Miner

Submissions for variant NM_000260.4(MYO7A):c.1846C>T (p.Arg616Trp) (rs369195493)

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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 RCV000036064 SCV000059716 uncertain significance not specified 2017-02-28 criteria provided, single submitter clinical testing The p.Arg616Trp variant in MYO7A has been reported in 2 individuals with sensori neural hearing loss and segregated with disease in one relative (Sommen 2016, LM M data). It has been identified in 4/9492 of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs369195493). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical signif icance of the p.Arg616Trp is uncertain.
Counsyl RCV000665882 SCV000790077 uncertain significance Deafness, autosomal recessive 2; Usher syndrome type 1 2017-03-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000036064 SCV000884212 uncertain significance not specified 2018-07-31 criteria provided, single submitter clinical testing The p.Arg616Trp variant (rs369195493) has been previously identified in cohort of patients with suspected autosomal recessive hearing loss (Sommen 2016); however, no clinically relevant details were provided to independently assess the significance of this observation. This variant is also listed in the ClinVar database as a variant of uncertain significance (Variation ID: 43160). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish Europeans populations of 0.03% (identified in 21 out of 79,010 chromosomes). The arginine at codon 616 is moderately conserved considering 13 species (Alamut software v2.9), although computational analyses suggest this variant has a significant effect on MYO7A protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). However, based on the available information, the clinical significance of the p.Arg616Trp variant cannot be determined with certainty.
Invitae RCV001060312 SCV001224992 uncertain significance not provided 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 616 of the MYO7A protein (p.Arg616Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs369195493, ExAC 0.05%). This variant has been observed in a cohort of individuals with non-syndromic hearing loss (PMID: 27068579). ClinVar contains an entry for this variant (Variation ID: 43160). 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"). 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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