Submissions for variant NM_001613.4(ACTA2):c.215C>T (p.Pro72Leu)

dbSNP: rs1060500134

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000459592	SCV000541644	likely pathogenic	Aortic aneurysm, familial thoracic 6	2021-09-29	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro72 amino acid residue in ACTA2. Other variant(s) that disrupt this residue have been observed in individuals with ACTA2-related conditions (PMID: 19409525), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt ACTA2 protein function. ClinVar contains an entry for this variant (Variation ID: 404178). This missense change has been observed in individuals with clinical features of thoracic aortic aneurysms and dissections (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 72 of the ACTA2 protein (p.Pro72Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.
Blueprint Genetics	RCV000788730	SCV000927951	likely pathogenic	not provided	2018-09-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001181622	SCV001346805	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-06-17	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 72 of the ACTA2 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 been reported in individuals with clinical features of thoracic aortic aneurysms and dissections (Clinvar SCV000541644.3). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Pro72Gln, has also been reported in individuals affected with aortic aneurysms and dissections (PMID: 19409525, 25759435), suggesting that proline at this position is important for protein function. 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.
GeneDx	RCV000788730	SCV001764175	uncertain significance	not provided	2020-05-04	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 404178; Landrum et al., 2016)
Ambry Genetics	RCV001181622	SCV004002034	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-28	criteria provided, single submitter	clinical testing	The p.P72L variant (also known as c.215C>T), located in coding exon 2 of the ACTA2 gene, results from a C to T substitution at nucleotide position 215. The proline at codon 72 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. 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.