ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.5499G>C (p.Glu1833Asp) (rs145252402)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182531 SCV000234879 uncertain significance not specified 2017-05-05 criteria provided, single submitter clinical testing The E1833D variant of uncertain significance in the MYH11 gene has been previously reported in an individual with a thoracic aortic aneurysm and bicuspid aortic valve, although no segregation data was provided (Poninska et al., 2016). This substitution occurs within a coiled coil region at a position that is conserved across species. Nevertheless, E1833D is a conservative amino acid substitution, which may not impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Moreover, E1833D has been observed in up to 0.07% of alleles from individuals of European background in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Ambry Genetics RCV000246107 SCV000317361 uncertain significance Cardiovascular phenotype 2017-09-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000589962 SCV000543718 likely benign not provided 2019-01-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589962 SCV000697649 likely benign not provided 2016-03-07 criteria provided, single submitter clinical testing Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a Glutamic acid (E) with Aspartic acid (D). Both residues are medium size and acidic, therefore this Glutamic acid to Aspartic acid substitution likely does not alter the physico-chemical properties of the protein. 2/4 in silico tools predict the variant to be neutral. It was found exclusively in the Non-Finnish European subcohort of the ExAC project at an allele frequency of 0.055% which exceeds 444 times the maximal expected allele frequency of a disease causing MYH11 allele (0.00013%) indicating a neutral impact. To our knowledge, the variant was not reported in affected individuals and in vitro/vivo studies assessing the impact of the variant on the function of the protein were not published either. A clinical diagnostic laboratory classified variant as Uncertain via ClinVar (without evidence to independently evaluate). Considering the prevalence of the variant in the ExAC, it was classified as Likely Benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589962 SCV000892480 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770691 SCV000902161 likely benign Thoracic aortic aneurysm and aortic dissection 2017-07-12 criteria provided, single submitter clinical testing
Color RCV000770691 SCV000911604 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-10-09 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the coiled coil myosin tail domain of the MYH11 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with thoracic aortic aneurysm (PMID: 27146836). This variant has also been identified in 96/276822 chromosomes (84/126348 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.

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