Submissions for variant NM_002474.3(MYH11):c.2600G>A (p.Arg867Gln)

gnomAD frequency: 0.00001  dbSNP: rs773993037

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001176852	SCV001340923	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 874 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 MYH11-related disorders in the literature. This variant has been identified in 4/251476 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001285384	SCV001471803	uncertain significance	Aortic aneurysm, familial thoracic 4	2020-03-02	criteria provided, single submitter	clinical testing	The MYH11 c.2600G>A; p.Arg867Gln variant (rs773993037), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 867 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Arg867Gln variant is uncertain at this time.
GeneDx	RCV002281166	SCV002569837	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics	RCV001176852	SCV002744469	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-11-29	criteria provided, single submitter	clinical testing	The p.R867Q variant (also known as c.2600G>A), located in coding exon 20 of the MYH11 gene, results from a G to A substitution at nucleotide position 2600. The arginine at codon 867 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001285384	SCV003490140	uncertain significance	Aortic aneurysm, familial thoracic 4	2023-06-04	criteria provided, single submitter	clinical testing	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. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 874 of the MYH11 protein (p.Arg874Gln). This variant is present in population databases (rs773993037, gnomAD 0.01%). 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: 918961). 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.
All of Us Research Program, National Institutes of Health	RCV001176852	SCV004823550	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 874 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 4/251476 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.
GenomeConnect, ClinGen	RCV001176852	SCV001423251	not provided	Familial thoracic aortic aneurysm and aortic dissection		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 02-27-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.