ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.4756C>G (p.Gln1586Glu) (rs794728680)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182561 SCV000234911 uncertain significance not provided 2018-08-20 criteria provided, single submitter clinical testing p.Gln1586Glu (CAG>GAG): c.4756 C>G in exon 33 of the MYH11 gene (NM_002474.2). A variant of unknown significance has been identified in the MYH11 gene. The Q1586E variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The Q1586E variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q1586E variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution occurs at a position that is conserved among mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, only one missense mutation in a nearby residue (R1583Q) has been reported in association with thoracic aortic aneurysm, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in TAAD panel(s).
Invitae RCV000641597 SCV000763239 uncertain significance Aortic aneurysm, familial thoracic 4 2017-11-01 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 1593 of the MYH11 protein (p.Gln1593Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYH11-related disease. ClinVar contains an entry for this variant (Variation ID: 201115). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; 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 RCV000778047 SCV000914161 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-04-09 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000641597 SCV001277599 uncertain significance Aortic aneurysm, familial thoracic 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000778047 SCV001333419 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2018-03-05 criteria provided, single submitter clinical testing

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