Submissions for variant NM_002474.3(MYH11):c.1924G>C (p.Ala642Pro)

dbSNP: rs371750065

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001187740	SCV001354611	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 649 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 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.
Ambry Genetics	RCV001187740	SCV002717448	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2025-01-28	criteria provided, single submitter	clinical testing	The p.A642P variant (also known as c.1924G>C), located in coding exon 15 of the MYH11 gene, results from a G to C substitution at nucleotide position 1924. The alanine at codon 642 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001187740	SCV004823616	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 649 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 cardiovascular 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005093956	SCV005813522	uncertain significance	Aortic aneurysm, familial thoracic 4	2024-03-31	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 649 of the MYH11 protein (p.Ala649Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 925657). 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.