Submissions for variant NM_002474.3(MYH11):c.633+1942T>C

gnomAD frequency: 0.00065  dbSNP: rs199755371

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000126977	SCV000170508	benign	not specified	2014-02-02	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	RCV000226159	SCV000285805	likely benign	Aortic aneurysm, familial thoracic 4	2024-01-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000126977	SCV000306214	likely benign	not specified		criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000226159	SCV000744027	likely benign	Aortic aneurysm, familial thoracic 4	2017-03-31	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000226159	SCV000745487	likely benign	Aortic aneurysm, familial thoracic 4	2015-12-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000126977	SCV000919818	benign	not specified	2018-09-04	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.654+10T>C alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 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 0.0004 in 276970 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 321-fold above the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.654+10T>C in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170346	SCV001332919	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-03-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812094	SCV002049034	likely benign	not provided	2022-03-01	criteria provided, single submitter	clinical testing