ClinVar Miner

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

gnomAD frequency: 0.00033  dbSNP: 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 2023-05-09 criteria provided, single submitter clinical testing Identified in a patient with optic atrophy with vision loss, oral ulcerations, arthralgia, and fatigue in the literature, although this patient was reported to have variants in multiple other genes with an unknown molecular diagnosis (McCreary et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 201037; ClinVar); This variant is associated with the following publications: (PMID: 31664448)
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 RCV000244427 SCV000319227 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 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 Laboratory Services, Illumina RCV000244427 SCV000395227 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, 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 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1766 of the MYH11 protein (p.Val1766Ile). This variant is present in population databases (rs138059405, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 201037). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH11 protein function with a negative predictive value of 95%. 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.
Eurofins Ntd Llc (ga) 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 Diagnostics, LLC DBA Color Health RCV000244427 SCV000904523 likely benign Familial thoracic aortic aneurysm and aortic dissection 2019-09-30 criteria provided, single submitter clinical testing
Illumina Laboratory Services, 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 2022-09-12 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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