Submissions for variant NM_002474.3(MYH11):c.3874G>C (p.Val1292Leu)

dbSNP: rs151058774

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000641583	SCV000763225	uncertain significance	Aortic aneurysm, familial thoracic 4	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1299 of the MYH11 protein (p.Val1299Leu). This variant is present in population databases (rs151058774, 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: 534147). 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.
Color Diagnostics, LLC DBA Color Health	RCV001176308	SCV001340225	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-02-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532984	SCV001748814	likely benign	not specified	2021-07-06	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.3895G>C (p.Val1299Leu) results in a conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251272 control chromosomes. The observed variant frequency is approximately 3.82 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 benign. To our knowledge, no occurrence of c.3895G>C in individuals affected with Thoracic Aortic Aneurysms And Dissections and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV001176308	SCV002622440	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-04-20	criteria provided, single submitter	clinical testing	The p.V1292L variant (also known as c.3874G>C), located in coding exon 28 of the MYH11 gene, results from a G to C substitution at nucleotide position 3874. The valine at codon 1292 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly 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.
GeneDx	RCV003117448	SCV003798792	uncertain significance	not provided	2022-12-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge