Submissions for variant NM_002474.3(MYH11):c.4034G>A (p.Arg1345Gln)

gnomAD frequency: 0.00013  dbSNP: rs150883363

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000415683	SCV001234426	uncertain significance	Aortic aneurysm, familial thoracic 4	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 1352 of the MYH11 protein (p.Arg1352Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs150883363, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). 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: 374961). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Color Diagnostics, LLC DBA Color Health	RCV001184302	SCV001350250	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1352 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 26/282210 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193458	SCV001362301	likely benign	not specified	2019-01-28	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.4055G>A (p.Arg1352Gln) results in a conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.4e-05 in 276540 control chromosomes. The observed variant frequency is approximately 75 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4055G>A in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV001184302	SCV002626241	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-11-02	criteria provided, single submitter	clinical testing	The p.R1345Q variant (also known as c.4034G>A), located in coding exon 29 of the MYH11 gene, results from a G to A substitution at nucleotide position 4034. The arginine at codon 1345 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. 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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000415683	SCV000493764	uncertain significance	Aortic aneurysm, familial thoracic 4	2015-08-13	no assertion criteria provided	clinical testing