ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.4994G>T (p.Arg1665Leu) (rs144813247)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182525 SCV000234872 uncertain significance not provided 2014-01-11 criteria provided, single submitter clinical testing The R1665L variant in the MYH11 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The R1665L variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The R1665 residue is conserved across species, and in silico analysis predicts R1665L is probably damaging to the protein structure/function. The R1665L 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. Nevertheless, no mutations affecting nearby residues have been reported in association with TAAD, indicating this residue may be tolerant of change.With the clinical and molecular information available at this time, we cannot definitively determine if R1665L is a disease-causing mutation or a rare benign variant. The variant is found in TAAD panel(s).
Invitae RCV000559002 SCV000641061 uncertain significance Aortic aneurysm, familial thoracic 4 2017-05-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 1672 of the MYH11 protein (p.Arg1672Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs144813247, ExAC 0.004%) but has not been reported in the literature in individuals with a MYH11-related disease. ClinVar contains an entry for this variant (Variation ID: 201081). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV001181815 SCV001347046 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-01-15 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000182525 SCV000925175 uncertain significance not provided 2016-12-29 no assertion criteria provided provider interpretation Genetic testing looked for variants in 15 genes associated with aneurysms and dissections: ACTA2, COL3A1, FBN1, FBN2, MAT2A, MYH11, MYLK, MYH11, PRKG1, SKI, SLC2A10, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2. Analysis also included deletion/duplication studies using comparative genomic hybridization for all of the genes mentioned above. Results reported on September 29, 2016 show that no disease-causing variants were found. However, a variant of unknown significance was found: See report below. p.Arg1665Leu (c.4994G>T) in the MYH11 gene (NM_002474.2) The lab classifies this variant as a variant of unknown significance. Given a lack of case data and presence in the general population we consider this variant a variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least one unrelated cases of FTAAD (not including this patient's family) that is listed in Clinvar with no additional data clinical data. The Arg at codon 1665 is not well conserved across species, and neither are neighboring amino acids. Pufferfish (His), Zebrafish (His), and fruit fly (Lys) all have different amino acids at this position. Other variants have not been reported in association with disease at this codon or in nearby codons. Missense variation has been reported as pathogenic and likely pathogenic in other individuals in clinvar. This variant is not in a known protein domain. There is significant variation at codon 1665 listed in the Genome Aggregation Consortium Dataset (gnomAD;, which currently includes variant calls on >126,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. 10 individuals have the same p.Arg1665Leu variant our patient has, 9 individuals have p.Arg1665His, and 12 individuals have p.Arg1665Cys. In total, 29 individuals have variation at this position for a total frequency of 1 in 4344 individuals in the general population which is likely too common for this variant to play a strong role in causing aneurysms and dissections.

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