ClinVar Miner

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

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000182562 SCV000052967 uncertain significance not specified 2020-10-19 criteria provided, single submitter clinical testing Variant summary: MYH11 c.4882A>C (p.Lys1628Gln) 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 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 79.5- fold 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 (examples- 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. Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneDx RCV000762209 SCV000234912 uncertain significance not provided 2021-06-24 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#36622; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 32238909, 29543232, 29907982)
Invitae RCV000554857 SCV000641058 uncertain significance Aortic aneurysm, familial thoracic 4 2019-12-19 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 been observed in individuals affected with aortic aneurysm (PMID: 29907982, 29543232). 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 2018-12-03 criteria provided, single submitter clinical testing The p.K1621Q variant (also known as c.4861A>C), located in coding exon 33 of the MYH11 gene, results from an A to C substitution at nucleotide position 4861. The lysine at codon 1621 is replaced by glutamine, an amino acid with similar properties, and is located in the coiled coil domain. This variant was detected in an individual with a thoracic aortic aneurysm (TAAD) and no known family history of the condition; however, clinical details were limited (Weerakkody R et al. Genet. Med., 2018 Mar;[Epub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
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
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000554857 SCV000745958 uncertain significance Aortic aneurysm, familial thoracic 4 2017-02-16 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659924 SCV000781828 uncertain significance Connective tissue disease 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
Cavalleri Lab, Royal College of Surgeons in Ireland RCV000554857 SCV001160810 uncertain significance Aortic aneurysm, familial thoracic 4 2019-12-11 criteria provided, single submitter research ACMG evidence PP2, PP3, PP5
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000611869 SCV001333418 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-02-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000611869 SCV001354763 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-11-04 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamine at codon 1628 of the MYH11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 29/282846 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.
Centre for Genomic and Experimental Medicine,University of Edinburgh RCV000611869 SCV000731234 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000762209 SCV001550154 uncertain significance not provided no assertion criteria provided clinical testing The MYH11 p.K1621Q variant was identified in an individual with thoracic aortic aneurysm/aortic dissection and an individual with suspected hereditary thoracic aortic disease (Weerakkody_2018_ PMID: 29543232; Overwater_2018_ PMID: 29907982). This variant was also identified in an individual with generalized epilepsy inherited from a presumably unaffected father without a family history of epilepsy (Benson_2020_PMID: 32238909). The variant was identified in dbSNP (ID: rs34321232) and ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and ten other submitters; and as likely pathogenic by Centre for Genomic and Experimental Medicine, University of Edinburgh). The variant was identified in control databases in 29 of 282846 chromosomes at a frequency of 0.0001025, and was observed at the highest frequency in the European (non-Finnish) population in 27 of 129166 chromosomes (freq: 0.0002090) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.K1621 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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