ClinVar Miner

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

gnomAD frequency: 0.00013  dbSNP: rs144813247
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182525 SCV000234872 uncertain significance not provided 2023-01-11 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: 26582918)
Invitae RCV000559002 SCV000641061 uncertain significance Aortic aneurysm, familial thoracic 4 2022-08-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1672 of the MYH11 protein (p.Arg1672Leu). This variant is present in population databases (rs144813247, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of thoracic aortic aneurysm and dissection (Invitae). 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. 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 RCV001181815 SCV001347046 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2022-12-19 criteria provided, single submitter clinical testing This missense variant replaces arginine with leucine at codon 1672 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 cardiovascular disorders in the literature. This variant has been identified in 9/282884 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.
Ambry Genetics RCV001181815 SCV002643550 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2021-03-24 criteria provided, single submitter clinical testing The p.R1665L variant (also known as c.4994G>T), located in coding exon 34 of the MYH11 gene, results from a G to T substitution at nucleotide position 4994. The arginine at codon 1665 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is 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.
Fulgent Genetics, Fulgent Genetics RCV002503709 SCV002817014 uncertain significance Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 2021-10-11 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; http://gnomad.broadinstitute.org/), 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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