Submissions for variant NM_002474.3(MYH11):c.3651+5_3651+11delinsG

dbSNP: rs371843272

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182470	SCV000234815	benign	Familial thoracic aortic aneurysm and aortic dissection	2014-06-17	criteria provided, single submitter	clinical testing	The variant is found in TAAD panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228545	SCV000285786	uncertain significance	Aortic aneurysm, familial thoracic 4	2016-01-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617147	SCV000317720	uncertain significance	Cardiovascular phenotype	2012-08-28	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589276	SCV000697643	benign	not specified	2021-05-24	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.3672+5_3672+11delinsG alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of approximately 0.0017 in 282664 control chromosomes, predominantly at a frequency of 0.019 within the African or African-American subpopulation in the gnomAD database, including 15 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is much higher than 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 African or African-American origin. c.3672+5_3672+11delinsG has been reported in the literature in at least one individual affected with thoracic aortic aneurysm (e.g. Bee_2012). This report does not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as benign/ likely benign (n=3) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000182470	SCV001333996	benign	Familial thoracic aortic aneurysm and aortic dissection	2019-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000182470	SCV001358524	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-10-02	criteria provided, single submitter	clinical testing