Submissions for variant NM_002474.3(MYH11):c.3560C>T (p.Thr1187Met)

gnomAD frequency: 0.00004  dbSNP: rs552818350

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000463204	SCV000543714	uncertain significance	Aortic aneurysm, familial thoracic 4	2023-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1194 of the MYH11 protein (p.Thr1194Met). This variant is present in population databases (rs552818350, gnomAD 0.007%). This missense change has been observed in individuals with MYH11-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 405474). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171281	SCV001333998	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-03-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001171281	SCV001356399	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1194 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 3/251450 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.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000584422	SCV000692246	uncertain significance	Bicuspid aortic valve	2015-11-19	no assertion criteria provided	clinical testing