Submissions for variant NM_002474.3(MYH11):c.5499G>C (p.Glu1833Asp)

gnomAD frequency: 0.00036  dbSNP: rs145252402

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589962	SCV000234879	likely benign	not provided	2021-03-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27146836)
Ambry Genetics	RCV000770691	SCV000317361	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-01-26	criteria provided, single submitter	clinical testing	The p.E1833D variant (also known as c.5499G>C), located in coding exon 37 of the MYH11 gene, results from a G to C substitution at nucleotide position 5499. The glutamic acid at codon 1833 is replaced by aspartic acid, an amino acid with highly similar properties, and is located in the coiled coil domain. This alteration was detected in an individual reported to have thoracic aortic aneurysm and a bicuspid aortic valve (Poninska JK et al. J Transl Med. 2016;14:115). This amino acid position is highly 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.
Invitae	RCV001085729	SCV000543718	likely benign	Aortic aneurysm, familial thoracic 4	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589962	SCV000892480	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	MYH11: PM2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770691	SCV000902161	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-07-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770691	SCV000911604	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000182531	SCV001338027	likely benign	not specified	2023-01-16	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.5520G>C (p.Glu1840Asp) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251074 control chromosomes, predominantly at a frequency of 0.00068 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 544 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. c.5520G>C has been reported in the literature in an individual affected with bicuspid aortic valve and thoracic aortic aneurysm, however without evidence for causality (Poninska_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Aortopathy. At-least one co-occurrence with another pathogenic variant associated with Loeys-Dietz syndrome has been observed at our laboratory ( TGFB2 c.895C>T , p.Arg299Trp), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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, n=5; VUS, n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001085729	SCV001440360	likely benign	Aortic aneurysm, familial thoracic 4	2019-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001085729	SCV001528068	uncertain significance	Aortic aneurysm, familial thoracic 4	2018-07-02	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute of Human Genetics, University Hospital Muenster	RCV002287385	SCV002577859	uncertain significance	Abnormality of connective tissue	2021-12-21	criteria provided, single submitter	clinical testing	ACMG categories: PM2,PP2,PP3,BP1
Ambry Genetics	RCV003352798	SCV004077564	likely benign	Inborn genetic diseases	2023-08-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000589962	SCV001977752	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000589962	SCV001978294	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000589962	SCV001979542	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000589962	SCV001979873	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000589962	SCV001980044	likely benign	not provided		no assertion criteria provided	clinical testing