ClinVar Miner

Submissions for variant NM_002474.3(MYH11):c.4861A>C (p.Lys1621Gln) (rs34321232)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000182562 SCV000052967 uncertain significance not specified 2019-05-30 criteria provided, single submitter clinical testing MYH11 c.4882A>C (p.Lys1628Gln, NM_001040113.1) results in a conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251470 control chromosomes. The observed variant frequency is approximately 80 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 benign. c.4882A>C has been reported in the literature in individuals affected with Aneurysm and Thoracic Aortic Disease (Weerakkody_2018, Overwater_2018). These reports do not provide unequivocal conclusions about association of the variant with Aortopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant.
GeneDx RCV000182562 SCV000234912 uncertain significance not specified 2016-12-15 criteria provided, single submitter clinical testing The K1621Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. In addition, this 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 K1621Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000554857 SCV000641058 uncertain significance Aortic aneurysm, familial thoracic 4 2018-01-23 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 1628 of the MYH11 protein (p.Lys1628Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant is present in population databases (rs34321232, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with MYH11-related disease. ClinVar contains an entry for this variant (Variation ID: 36622). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000619199 SCV000739203 uncertain significance Cardiovascular phenotype 2016-05-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000554857 SCV000744016 uncertain significance Aortic aneurysm, familial thoracic 4 2016-02-09 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000659924 SCV000781828 uncertain significance Connective tissue disorder 2016-11-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000762209 SCV000892483 uncertain significance not provided 2018-04-01 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000762209 SCV000987635 uncertain significance not provided criteria provided, single submitter clinical testing
Mendelics RCV000554857 SCV001139961 uncertain significance Aortic aneurysm, familial thoracic 4 2019-05-28 criteria provided, single submitter clinical testing
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000611869 SCV000731234 likely pathogenic Thoracic aortic aneurysm and aortic dissection no assertion criteria provided research
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000554857 SCV000745958 uncertain significance Aortic aneurysm, familial thoracic 4 2017-02-16 no assertion criteria provided clinical testing

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