Submissions for variant NM_002474.3(MYH11):c.5666C>T (p.Ala1889Val)

gnomAD frequency: 0.00006  dbSNP: rs369950711

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182535	SCV000234883	uncertain significance	not provided	2023-09-05	criteria provided, single submitter	clinical testing	Has been reported as a variant of uncertain significance (listed as p.(A1896V) using alternate nomenclature) in a male with aortic dissection (Hicks et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21529752, 29510914)
Ambry Genetics	RCV000771912	SCV000318736	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2022-08-03	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.
Color Diagnostics, LLC DBA Color Health	RCV000771912	SCV000904678	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-09-27	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1896 of the MYH11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual referred for suspected genetic vascular disease (PMID: 29510914). This variant has been identified in 13/276966 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV000814301	SCV000954704	uncertain significance	Aortic aneurysm, familial thoracic 4	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1896 of the MYH11 protein (p.Ala1896Val). This variant is present in population databases (rs369950711, gnomAD 0.01%). This missense change has been observed in individual(s) with thoracic aortic aneurysm and dissection (PMID: 29510914). ClinVar contains an entry for this variant (Variation ID: 201090). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH11 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV000814301	SCV001279557	uncertain significance	Aortic aneurysm, familial thoracic 4	2018-01-15	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000771912	SCV001333413	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-10-16	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000814301	SCV001428666	uncertain significance	Aortic aneurysm, familial thoracic 4	2019-05-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000182535	SCV004562973	uncertain significance	not provided	2023-09-08	criteria provided, single submitter	clinical testing