ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.4603C>T (p.Arg1535Trp) (rs143402648)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414111 SCV000490646 uncertain significance not specified 2016-08-12 criteria provided, single submitter clinical testing The R1535W variant in the MYH11 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1535W variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1535W 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1535W as a variant of uncertain significance.
Invitae RCV000556757 SCV000641044 uncertain significance Aortic aneurysm, familial thoracic 4 2018-08-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1542 of the MYH11 protein (p.Arg1542Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs143402648, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with MYH11-related disease. ClinVar contains an entry for this variant (Variation ID: 372423). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Fulgent Genetics,Fulgent Genetics RCV000556757 SCV000896505 uncertain significance Aortic aneurysm, familial thoracic 4 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000776309 SCV000911630 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-05-11 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in coiled coil myosin tail domain of the MYH11 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has the variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 34/277100 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Blueprint Genetics RCV000788492 SCV000927634 uncertain significance not provided 2018-04-18 criteria provided, single submitter clinical testing

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