ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.5275G>A (p.Val1759Ile) (rs138059405)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656918 SCV000234823 uncertain significance not provided 2017-11-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH11 gene. The V1759I variant has not been published as pathogenic or been reported as benign to our knowledge. The V1759I variant is observed at a frequency of 0.05% (58/126,442 alleles) in individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016). This variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for Marfan/TAAD and HDCT genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The V1759I 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 analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000239107 SCV000296988 uncertain significance Aortic aneurysm, familial thoracic 4 2015-10-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617123 SCV000319227 uncertain significance Cardiovascular phenotype 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
Illumina Clinical Services Laboratory,Illumina RCV000244427 SCV000395227 uncertain significance Thoracic aortic aneurysm and aortic dissection 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000405397 SCV000395228 uncertain significance Lissencephaly, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000239107 SCV000641068 uncertain significance Aortic aneurysm, familial thoracic 4 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1766 of the MYH11 protein (p.Val1766Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs138059405, 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: 201037). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656918 SCV000703997 uncertain significance not provided 2017-01-03 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000244427 SCV000902164 likely benign Thoracic aortic aneurysm and aortic dissection 2017-10-19 criteria provided, single submitter clinical testing
Color RCV000244427 SCV000904523 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-10-03 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 suggest that this variant may not impact 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 this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 70/273502 chromosomes (58/126442 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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