Submissions for variant NM_002474.3(MYH11):c.2320G>A (p.Val774Ile)

dbSNP: rs147897132

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001180584	SCV000739206	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-05-17	criteria provided, single submitter	clinical testing	The p.V774I variant (also known as c.2320G>A), located in coding exon 18 of the MYH11 gene, results from a G to A substitution at nucleotide position 2320. The valine at codon 774 is replaced by isoleucine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs147897132. Based on data from ExAC, the A allele has an overall frequency less than 0.01% (3/106205). Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/12994) total alleles studied and 0.01% (1/8600) European American alleles. Allele frequency data for this nucleotide position is not currently available from the 1000 Genomes Project. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001180584	SCV001345543	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-11-26	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 781 of the MYH11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 been identified in 7/251496 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.
GeneDx	RCV002307561	SCV002601104	uncertain significance	not provided	2023-11-07	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531831	SCV003258427	uncertain significance	Aortic aneurysm, familial thoracic 4	2025-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 781 of the MYH11 protein (p.Val781Ile). This variant is present in population databases (rs147897132, gnomAD 0.006%). 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: 519937). 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.
All of Us Research Program, National Institutes of Health	RCV001180584	SCV004823575	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 781 of the MYH11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 been identified in 7/251496 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.