Submissions for variant NM_002474.3(MYH11):c.2049C>T (p.His683=)

gnomAD frequency: 0.00061  dbSNP: rs150924100

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205608	SCV000261649	likely benign	Aortic aneurysm, familial thoracic 4	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001178105	SCV000317323	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2015-05-11	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.
Illumina Laboratory Services, Illumina	RCV000205608	SCV000395373	uncertain significance	Aortic aneurysm, familial thoracic 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000205608	SCV000745481	likely benign	Aortic aneurysm, familial thoracic 4	2017-06-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780513	SCV000917827	benign	not specified	2018-05-07	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.2070C>T alters a non-conserved nucleotide resulting in a synonymous change. 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 0.00053 in 276362 control chromosomes. The observed variant frequency is approximately 423 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.2070C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, three of whom have classified the variant as "Likely Benign". Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000858214	SCV001150836	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	MYH11: BP4, BP7
Color Diagnostics, LLC DBA Color Health	RCV001178105	SCV001342460	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-11-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000858214	SCV001940801	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001178105	SCV002042925	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-04-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000858214	SCV002049341	likely benign	not provided	2023-10-19	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000205608	SCV000745970	likely benign	Aortic aneurysm, familial thoracic 4	2014-11-19	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000858214	SCV001932676	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000858214	SCV001955718	likely benign	not provided		no assertion criteria provided	clinical testing