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

gnomAD frequency: 0.00174  dbSNP: rs150759461

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001092826	SCV000234894	likely benign	not provided	2021-06-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22968129, 16444274, 25407000, 24337657, 10854329, 22511748, 25433566, 26893369, 27879251, 27153395, 29494672, 17956658, 17666408, 14722581, 10199307, 7923625, 26792327, 25424711, 24676022, 27418595, 26017485, 25637381, 26332594, 27535533, 29961567, 32220188, 32068640)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206298	SCV000261650	likely benign	Aortic aneurysm, familial thoracic 4	2025-02-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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	RCV001092826	SCV000604349	likely benign	not provided	2024-05-09	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
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, 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 disorder	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 Diagnostics, LLC DBA Color Health	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 Center for Human Genetics Tuebingen	RCV001092826	SCV001249520	likely benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	MYH11: PP3, BS2
Illumina Laboratory Services, 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	2023-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Ambry Genetics	RCV000776119	SCV002673954	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-03-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224171	SCV003920234	uncertain significance	Aortic aneurysm, familial thoracic 4; Visceral myopathy 2; Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	2021-03-30	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.
All of Us Research Program, National Institutes of Health	RCV000776119	SCV005430710	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2024-09-23	criteria provided, single submitter	clinical testing
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, Amsterdam University Medical Center	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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001092826	SCV001799022	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003935256	SCV004756302	likely benign	MYH11-related disorder	2020-10-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).