Submissions for variant NM_001613.4(ACTA2):c.720G>C (p.Lys240Asn)

dbSNP: rs727502878

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150127	SCV000196973	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2017-09-20	criteria provided, single submitter	clinical testing	The p.Lys240Asn variant in ACTA2 has been identified by our laboratory in 1 indi vidual with familial thoracic aortic aneurysms/dissections (TAAD) and segregated with disease in at least 5 affected relatives including 3 obligate carriers (Pr evention Genetics and LMM, unpublished data). It was absent from large populatio n studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are r equired to fully establish its clinical significance, the p.Lys240Asn variant is likely pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000622410	SCV000740532	likely pathogenic	Aortic aneurysm, familial thoracic 6	2017-01-06	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000788670	SCV000927862	likely pathogenic	not provided	2018-08-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000622410	SCV000938949	uncertain significance	Aortic aneurysm, familial thoracic 6	2019-06-17	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with asparagine at codon 240 of the ACTA2 protein (p.Lys240Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. 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. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in a family affected with thoracic aortic aneurysm and dissection (Invitae). ClinVar contains an entry for this variant (Variation ID: 162701). This variant is not present in population databases (ExAC no frequency).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000150127	SCV002042324	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-04-20	criteria provided, single submitter	clinical testing