ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.739C>T (p.Arg247Cys) (rs150759461)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182546 SCV000234894 likely benign not specified 2017-09-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000206298 SCV000261650 likely benign Aortic aneurysm, familial thoracic 4 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000251088 SCV000318112 uncertain significance Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000182546 SCV000539829 likely benign not specified 2016-03-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.3% European; ClinVar: 2 VUS, 1 LB
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000206298 SCV000604349 likely benign Aortic aneurysm, familial thoracic 4 2018-07-05 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000206298 SCV000744026 likely benign Aortic aneurysm, familial thoracic 4 2016-10-19 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000206298 SCV000745486 likely benign Aortic aneurysm, familial thoracic 4 2015-07-22 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659901 SCV000781803 uncertain significance Connective tissue disease 2016-11-01 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000206298 SCV000898839 uncertain significance Aortic aneurysm, familial thoracic 4 2018-11-30 criteria provided, single submitter clinical testing MYH11 NM_002474.2 exon 7 p.Arg247Cys (c.739C>T): This variant has been reported in the literature (also referred to as p.Arg254Cys) in at least one individual with abdominal aortic aneurysm, segregating with disease in one affected family member (Van de Luijtgaarden 2015 PMID:26017485). This variant is present in 0.3% (393/129162) of European alleles in the Genome Aggregation Database, including 2 homozygotes (http://gnomad.broadinstitute.org/variant/16-15872688-G-A). This variant is also present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:161317). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Kuang 2012 PMID: 22511748; Bellini 2015 PMID: 25433566). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Color RCV000776119 SCV000910997 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-04-16 criteria provided, single submitter clinical testing
Mendelics RCV000206298 SCV001139962 benign Aortic aneurysm, familial thoracic 4 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001092826 SCV001249520 uncertain significance not provided 2019-11-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000206298 SCV001278181 likely benign Aortic aneurysm, familial thoracic 4 2018-03-23 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000776119 SCV001332918 likely benign Familial thoracic aortic aneurysm and aortic dissection 2019-04-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000182546 SCV001362299 likely benign not specified 2019-10-22 criteria provided, single submitter clinical testing Variant summary: MYH11 c.760C>T (p.Arg254Cys, also known as c.739C>T/p.Arg247Cys) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 282840 control chromosomes, predominantly at a frequency of 0.003 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2400 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.760C>T, has been reported in the literature in at least one family with 2 affected individuals (Van de Luijtgaarden_2015), and in patients with aortic disease and no family history (Kuang_2012). These reports however do not provide unequivocal conclusions about association of the variant with Aortopathy. Publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the p.Arg247Cys substitution decreases the ATPase activity (actin-activated), and the rate of actin filament sliding, and in a knock-in mouse model the mutant aorta displayed a decreased contractile response, but there was no overall vascular phenotype under normal conditions in either homozygous or heterozygous mice (Kuang_2012, Huang_2018). However, the homozygous mutant knock-in mice were more vulnerable to alterations in hemodynamic loading (Bellini_2015), or developed aortic dilation when crossed with the ACTA2 +/- mice, indicating that two variants not known to cause disease may lead to aortic enlargement in combination (Kwartler_2018). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign 7x, VUS 2x). Based on the evidence outlined above, the variant is unlikely to cause familial thoracic aortic disease, but more evidence is required to determine if it might represent a low penetrance risk variant, therefore it was classified as likely benign.
CSER _CC_NCGL, University of Washington RCV000148692 SCV000190419 likely benign Altered myosin contractile function 2014-06-01 no assertion criteria provided research
Blueprint Genetics RCV000157329 SCV000207066 uncertain significance Loeys-Dietz syndrome 2014-04-11 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000206298 SCV000745975 likely benign Aortic aneurysm, familial thoracic 4 2014-02-04 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000844919 SCV000986726 not provided Aortic aneurysm, familial thoracic 4; Congenital aneurysm of ascending aorta no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 03/28/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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