ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.3973C>G (p.Gln1325Glu) (rs150033906)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182514 SCV000234860 uncertain significance not specified 2016-09-08 criteria provided, single submitter clinical testing The Q1325E variant of uncertain significance in the MYH11 gene has not been published as a pathogenic or benign variant to our knowledge. This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and occurs at a position conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the Q1325E variant is damaging to the protein structure/function. Although this variant has been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for genetic testing for Marfan syndrome, TAAD, and related disorders at GeneDx, thus far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. While the Q1325E variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, the Exome Aggregation Consortium reports Q1325E was observed in 0.54% of alleles from individuals of Finnish background, indicating it may be a rare benign variant in this population. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000243337 SCV000317810 likely benign Cardiovascular phenotype 2018-10-26 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000641635 SCV000763278 benign Aortic aneurysm, familial thoracic 4 2020-03-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000182514 SCV000919824 benign not specified 2018-12-11 criteria provided, single submitter clinical testing Variant summary: MYH11 c.3994C>G (p.Gln1332Glu) results in a conservative amino acid change located in the Myosin tail domain 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 0.00067 in 276842 control chromosomes, predominantly at a frequency of 0.005 within the Finnish subpopulation in the gnomAD database. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 4000 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. To our knowledge, no occurrence of c.3994C>G in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as uncertain significance and once as benign. Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171279 SCV001333990 benign Familial thoracic aortic aneurysm and aortic dissection 2019-02-26 criteria provided, single submitter clinical testing
Color Health, Inc RCV001171279 SCV001340867 likely benign Familial thoracic aortic aneurysm and aortic dissection 2018-11-30 criteria provided, single submitter clinical testing

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