Submissions for variant NM_002474.3(MYH11):c.5635G>A (p.Val1879Ile)

gnomAD frequency: 0.00032  dbSNP: rs138206921

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478153	SCV000565733	likely benign	not provided	2021-05-27	criteria provided, single submitter	clinical testing
Invitae	RCV001089216	SCV000641076	likely benign	Aortic aneurysm, familial thoracic 4	2023-12-31	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659929	SCV000781833	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000777832	SCV000913831	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-06-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000777832	SCV002652873	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-11-17	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235238	SCV003934714	likely benign	not specified	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.5656G>A (p.Val1886Ile) results in a conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 250956 control chromosomes. The observed variant frequency is approximately 16-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Thoracic Aortic Aneurysms And Dissections phenotype (1.3e-05), strongly suggesting that the variant is benign. c.5656G>A has been reported in the literature in an individual affected with Thoracic Aortic Aneurysms without strong evidence of causality (Salmasi_2022). This report does not provide unequivocal conclusions about association of the variant with Thoracic Aortic Aneurysms And Dissections. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35830949). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.