Submissions for variant NM_002474.3(MYH11):c.5581G>A (p.Glu1861Lys)

gnomAD frequency: 0.00006  dbSNP: rs139418145

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182533	SCV000234881	uncertain significance	not provided	2019-08-22	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV001185744	SCV001352011	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-09-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1868 of the MYH11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 6/282758 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.
Ambry Genetics	RCV001185744	SCV002650954	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-06-15	criteria provided, single submitter	clinical testing	The p.E1861K variant (also known as c.5581G>A), located in coding exon 38 of the MYH11 gene, results from a G to A substitution at nucleotide position 5581. The glutamic acid at codon 1861 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000182533	SCV003817176	uncertain significance	not provided	2022-09-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003514324	SCV004299342	uncertain significance	Aortic aneurysm, familial thoracic 4	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1868 of the MYH11 protein (p.Glu1868Lys). This variant is present in population databases (rs139418145, gnomAD 0.02%). 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: 201088). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
All of Us Research Program, National Institutes of Health	RCV001185744	SCV004815512	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1868 of the MYH11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/282758 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.