ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.3757AAG[3] (p.Lys1256del) (rs730880147)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254668 SCV000234904 uncertain significance not provided 2018-12-03 criteria provided, single submitter clinical testing The c.3766_3768delAAG variant was initially reported in a Dutch family with TAAD and patent ductus arteriosus (PDA), though failed to completely segregate with disease in family members (Harakalova et al., 2013). In addition, Imai et al. (2015) reported c.3766_3768delAAG in two independent Japanese families with TAAD. Although segregation studies were not performed in the second family, the c.3766_3768delAAG variant segregated with TAAD in two siblings from the first family and was also identified in another pediatric family member with PDA but no TAAD (Imai et al., 2015). Wooderchak-Donahue et al. (2015) identified c.3766_3768delAAG in two samples referred for aortopathy panel testing, though one individual harbored an additional FBN1 variant. In addition, Gago-Díaz et al. (2017) identified c.3766_3768delAAG in a patient with Stanford Type A aortic dissection and sudden cardiac death who also harbored another MYH11 variant of uncertain significance. Furthermore, this variant has been identified in multiple probands referred to GeneDx for Marfan syndorme/TAAD testing, however, several harbored co-occurring cardiogenetic variants, and no family segregation studies have been performed to our knowledge.The c.3766_3768delAAG variant is predicted to result in the deletion of one amino acid (p.Lys1256del) at a residue that is conserved across species. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, this variant is observed in 8/111,676 (0.007%) alleles from individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Ambry Genetics RCV000617047 SCV000319471 uncertain significance Cardiovascular phenotype 2019-11-21 criteria provided, single submitter clinical testing The c.3766_3768delAAG variant (also known as p.K1256del) is located in coding exon 27 of the MYH11 gene. This variant results from an in-frame AAG deletion at nucleotide positions 3766 to 3768. This results in the in-frame deletion of a lysine at codon 1256. This variant, sometimes described as c.3787_3789delAAG (p.K1236del), has been reported in individuals with thoracic aortic aneurysms and dissections (TAAD) and patent ductus arteriosus (PDA), including segregation with disease in at least one family (Proost D et al. Hum. Mutat., 2015 Aug;36:808-14; Imai Y et al. Int. J. Cardiol., 2015 Sep;195:290-2; Yeung KK et al. Hum. Mutat., 2017 Apr;38:439-450). This variant was also observed in an affected family with four individuals affected with PDA and two affected with TAAD; however, one individual with PDA and one individual with TAAD did not have this variant (Harakalova M, Eur. J. Hum. Genet. 2013 May; 21(5):487-93).<span style="color:rgb(34, 34, 34); font-family:arial,sans-serif"> In addition, this alteration was identified twice in a cohort of individuals referred for aortopathy panel testing, one of whom had aortic dilation and dissection and also carried the FBN1 p.T2149Ifs*11 mutation (Wooderchak-Donahue W et al. Am. J. Med. Genet. A, 2015 Aug;167A:1747-57). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious<span style="color:rgb(255, 0, 0)"> by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000466385 SCV000543703 uncertain significance Aortic aneurysm, familial thoracic 4 2020-10-29 criteria provided, single submitter clinical testing This variant, c.3787_3789delAAG, results in the deletion of 1 amino acid of the MYH11 protein (p.Lys1263del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs730880147, ExAC 0.01%). This variant has been reported in families affected with thoracic aortic aneurysms and dissections (TAAD) and patent ductus arteriosus (PDA) (PMID: 22968129, 26056961). But in one family this variant failed to segregate with disease (PMID: 22968129). In addition, this variant has been observed in individuals referred for aortopathy genetic testing (PMID: 25944730). However, in one individual with Marfan syndrome, a pathogenic allele was also identified in FBN1, which suggests that this c.3787_3789delAAG variant was not the primary cause of disease. This variant is also known as c.3766_3768delAAG (p.Lys1256del) in the literature. ClinVar contains an entry for this variant (Variation ID: 180420). This variant has been reported to affect MYH11 protein function (PMID: 28074631). 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.
Institute of Human Genetics,University Medical Center Hamburg-Eppendorf RCV000157334 SCV000897677 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2018-11-20 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000254668 SCV000927633 uncertain significance not provided 2019-05-08 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000254668 SCV001150826 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000157334 SCV001333993 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2017-11-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000157334 SCV001340636 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-04-16 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157334 SCV000207071 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2014-09-18 no assertion criteria provided clinical testing

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