ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656918 SCV000234823 uncertain significance not provided 2021-05-05 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 201037; Landrum et al., 2016)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,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 2019-12-19 criteria provided, single submitter clinical testing The p.V1759I variant (also known as c.5275G>A), located in coding exon 36 of the MYH11 gene, results from a G to A substitution at nucleotide position 5275. The valine at codon 1759 is replaced by isoleucine, an amino acid with highly similar properties, and is located in the coiled coil domain. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Clinical Services Laboratory,Illumina RCV000244427 SCV000395227 uncertain significance Familial 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 2020-10-08 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 Familial thoracic aortic aneurysm and aortic dissection 2017-10-19 criteria provided, single submitter clinical testing
Color Health, Inc RCV000244427 SCV000904523 likely benign Familial thoracic aortic aneurysm and aortic dissection 2019-09-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000239107 SCV001277493 uncertain significance Aortic aneurysm, familial thoracic 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001553753 SCV001774744 likely benign not specified 2021-07-12 criteria provided, single submitter clinical testing Variant summary: MYH11 c.5296G>A (p.Val1766Ile) results in a conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 247728 control chromosomes, predominantly at a frequency of 0.00043 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 34 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Thoracic Aortic Aneurysms And Dissections phenotype (1.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.5296G>A has been reported in the literature in one individual with suspected genetic neuroinflammatory disorders (McCreary_2019). The report does not provide unequivocal conclusions about association of the variant with Thoracic Aortic Aneurysms And Dissections. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=7) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.

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