ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.5516C>T (p.Ala1839Val) (rs112948385)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724061 SCV000229950 uncertain significance not provided 2014-09-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617124 SCV000319243 uncertain significance Cardiovascular phenotype 2018-05-21 criteria provided, single submitter clinical testing Insufficient evidence
Illumina Clinical Services Laboratory,Illumina RCV000252424 SCV000395207 uncertain significance Thoracic aortic aneurysm and aortic dissection 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000390537 SCV000395208 uncertain significance Lissencephaly, Recessive 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000724061 SCV000536457 uncertain significance not provided 2017-01-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH11 gene. The A1839V variant has not been published as pathogenic or been reported as benign to our knowledge. The A1839V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved in mammals. However, the A1839V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000456952 SCV000543719 uncertain significance Aortic aneurysm, familial thoracic 4 2016-05-05 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1846 of the MYH11 protein (p.Ala1846Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs112948385, ExAC 0.06%) but has not been reported in the literature in individuals with a MYH11-related disease. ClinVar contains an entry for this variant (Variation ID: 197069). 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: "Benign"; Align-GVGD: "Class C55"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Human Genetics, Inc RCV000659928 SCV000781832 likely benign Connective tissue disorder 2016-11-01 criteria provided, single submitter clinical testing
Color RCV000252424 SCV000904490 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-07-09 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 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 52/276938 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000724061 SCV000925174 uncertain significance not provided 2016-07-22 no assertion criteria provided provider interpretation p.Ala1846Val (c.5537C>T) in the MYH11 gene (NM_001040113.1) Given the lack of case data and allele frequency in ExAC we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). MYH11 has been associated with autosomal dominant thoracic aortic aneurysms and dissection. Per the lab report and our own searches, the variant has not been reported in individuals with aneurysms and dissections. The variant was reported online in 26 of 60536 individuals in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 20th, 2016). Specifically, the variant was observed in Latinos, Europeans, East Asians, and Africans. The highest allele frequency was in the "other" group (0.002217). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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