Submissions for variant NM_002474.3(MYH11):c.5375G>A (p.Arg1792Gln)

gnomAD frequency: 0.00002  dbSNP: rs751495086

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182529	SCV000234877	uncertain significance	not provided	2024-05-08	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 has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18798114)
Color Diagnostics, LLC DBA Color Health	RCV001186484	SCV001352920	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1799 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 8/251116 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001308821	SCV001498291	uncertain significance	Aortic aneurysm, familial thoracic 4	2024-07-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1799 of the MYH11 protein (p.Arg1799Gln). This variant is present in population databases (rs751495086, gnomAD 0.007%). 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: 201084). 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.
Ambry Genetics	RCV001186484	SCV002645141	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-11-27	criteria provided, single submitter	clinical testing	The p.R1792Q variant (also known as c.5375G>A), located in coding exon 37 of the MYH11 gene, results from a G to A substitution at nucleotide position 5375. The arginine at codon 1792 is replaced by glutamine, an amino acid with highly similar properties, and is located in the coiled coil domain. 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 alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001186484	SCV004815553	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-05-14	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces arginine with glutamine at codon 1799 of the MYH11 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 7/245908 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.