Submissions for variant NM_002474.3(MYH11):c.4150G>C (p.Ala1384Pro)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003515199	SCV004323712	uncertain significance	Aortic aneurysm, familial thoracic 4	2024-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1391 of the MYH11 protein (p.Ala1391Pro). This variant is present in population databases (rs775802674, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. 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.
Color Diagnostics, LLC DBA Color Health	RCV003527747	SCV004359366	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 1391 of the MYH11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 5/282382 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	RCV003527747	SCV005018878	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-07-30	criteria provided, single submitter	clinical testing	The p.A1384P variant (also known as c.4150G>C), located in coding exon 30 of the MYH11 gene, results from a G to C substitution at nucleotide position 4150. The alanine at codon 1384 is replaced by proline, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.