Submissions for variant NM_002474.3(MYH11):c.429G>A (p.Lys143=)

gnomAD frequency: 0.00056  dbSNP: rs200672270

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082555	SCV000285791	likely benign	Aortic aneurysm, familial thoracic 4	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000253932	SCV000306194	likely benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000249343	SCV000318521	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2015-09-09	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.
Illumina Laboratory Services, Illumina	RCV001082555	SCV000395401	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.
CeGaT Center for Human Genetics Tuebingen	RCV000513448	SCV000608754	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	MYH11: BP4
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659900	SCV000781802	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000249343	SCV000902170	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2021-01-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000249343	SCV000911584	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-06-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001082555	SCV001440938	likely benign	Aortic aneurysm, familial thoracic 4	2019-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000253932	SCV001467981	benign	not specified	2020-12-29	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.429G>A alters a non-conserved nucleotide resulting in a synonymous change. 3/4 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 0.00042 in 251490 control chromosomes. The observed variant frequency is approximately 33.7-fold 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. To our knowledge, no occurrence of c.429G>A in individuals affected with Thoracic Aortic Aneurysms And Dissections and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as likely benign (n=7) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000513448	SCV001888074	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000513448	SCV004564674	likely benign	not provided	2023-10-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000249343	SCV004816859	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2024-02-05	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000513448	SCV001978411	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513448	SCV001980267	likely benign	not provided		no assertion criteria provided	clinical testing