ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.5767G>A (p.Ala1923Thr) (rs571504063)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000756379 SCV000234885 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing The A1923T variant in the MYH11 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 10/33,580 (0.0269%) alleles from individuals of Latino background, and 17/245,182 global alleles (0.0069%), in large population cohorts (Lek et al., 2016). The A1923T 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret A1923T as a variant of uncertain significance, which may be related to the suspected connective tissue disorder reported in this individual and her father and sister.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756379 SCV000884174 uncertain significance not provided 2017-07-04 criteria provided, single submitter clinical testing
Invitae RCV000796819 SCV000936347 uncertain significance Aortic aneurysm, familial thoracic 4 2018-10-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1930 of the MYH11 protein (p.Ala1930Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs571504063, ExAC 0.03%), 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: 201092). 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: "Benign"; 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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