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 2019-08-22 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV001085729 SCV000543718 likely benign Aortic aneurysm, familial thoracic 4 2019-12-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589962 SCV000892480 uncertain significance not provided 2019-11-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770691 SCV000902161 likely benign Familial thoracic aortic aneurysm and aortic dissection 2017-07-12 criteria provided, single submitter clinical testing
Color RCV000770691 SCV000911604 likely benign Familial thoracic aortic aneurysm and aortic dissection 2019-11-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000182531 SCV001338027 likely benign not specified 2020-01-06 criteria provided, single submitter clinical testing Variant summary: MYH11 c.5520G>C (p.Glu1840Asp) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251074 control chromosomes, predominantly at a frequency of 0.00068 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 550 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.5520G>C has been reported in the literature in an individual affected with bicuspid aortic valve and thoracic aortic aneurysm, however without evidence for causality (Poninska_2016). This report does not provide unequivocal conclusions about association of the variant with Aortopathy. Co-occurrence with another pathogenic variant has been reported (TGFB2 c.895C>T (p.Arg299Trp), in an LCA internal sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (4x) or likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.

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