ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.5095G>A (p.Ala1699Thr)

gnomAD frequency: 0.00001  dbSNP: rs200410021
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000557522 SCV000641064 uncertain significance Aortic aneurysm, familial thoracic 4 2022-09-01 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1706 of the MYH11 protein (p.Ala1706Thr). This variant is present in population databases (rs200410021, gnomAD 0.005%). 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: 465746). 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 disruptive. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780515 SCV000917831 uncertain significance not specified 2018-09-10 criteria provided, single submitter clinical testing Variant summary: MYH11 c.5116G>A (p.Ala1706Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 119390 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5116G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV001176125 SCV001339992 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-04-02 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 1706 of the MYH11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH11-related disorders in the literature. This variant has been identified in 6/249518 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx RCV002254933 SCV002526143 uncertain significance not provided 2022-05-26 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
Ambry Genetics RCV001176125 SCV002640539 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-10-27 criteria provided, single submitter clinical testing The p.A1699T variant (also known as c.5095G>A), located in coding exon 35 of the MYH11 gene, results from a G to A substitution at nucleotide position 5095. The alanine at codon 1699 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. 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.

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