Submissions for variant NM_002474.3(MYH11):c.861G>A (p.Met287Ile)

dbSNP: rs1371371071

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001068471	SCV001233584	uncertain significance	Aortic aneurysm, familial thoracic 4	2019-03-04	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with MYH11-related conditions. 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 294 of the MYH11 protein (p.Met294Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine.
Color Diagnostics, LLC DBA Color Health	RCV001176324	SCV001340262	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 294 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 not been identified 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.
All of Us Research Program, National Institutes of Health	RCV001176324	SCV004816822	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-09-17	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the myosin motor domain of the MYH11 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Ambry Genetics	RCV001176324	SCV005453422	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-08-28	criteria provided, single submitter	clinical testing	The p.M287I variant (also known as c.861G>A), located in coding exon 7 of the MYH11 gene, results from a G to A substitution at nucleotide position 861. The methionine at codon 287 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.