ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.3637G>A (p.Val1213Met) (rs368390254)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000455436 SCV000539843 uncertain significance not specified 2016-04-25 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 proband, no segs in HGMD; ExAC: 5/27770 European chromosomes
Invitae RCV000472608 SCV000550005 uncertain significance Aortic aneurysm, familial thoracic 7 2017-07-09 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1213 of the MYLK protein (p.Val1213Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs368390254, ExAC 0.02%). This variant has been reported in individuals affected with thoracic aortic aneurysm or dissection (PMID: 21055718, 10612827). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
GeneDx RCV000455436 SCV000568809 uncertain significance not specified 2017-02-09 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYLK gene. The V1213M variant has been reported in one patient with familial TAAD; however, familial segregation information was not available (Wang et al., 2010). The V1213M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species and where methionine is present as the wild type in several species. Furthermore, in silico analysis suggests that this variant likely does not alter the protein structure/function. Nevertheless, the V1213M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Ambry Genetics RCV000618715 SCV000739314 uncertain significance Cardiovascular phenotype 2016-11-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756401 SCV000884201 uncertain significance not provided 2018-02-13 criteria provided, single submitter clinical testing The MYLK c.3637G>A; p.Val1213Met variant (rs368390254) has been reported in a single family with thoracic aortic aneurysms or aortic dissections (TAAD), but insufficient segregation data was available to determine whether or not the variant is associated with aortic disease (Wang 2010). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.009% (identified on 23 out of 255,410 chromosomes) and is classified as a variant of unknown significance in ClinVar (ID: 403212). The valine at position 1213 is weakly conserved, considering 12 species, and a methionine is found in this position in several species, suggesting this variant is evolutionarily tolerated. Computational analyses of the effects of the p.Val1213Met variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Val1213Met variant cannot be determined with certainty.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000582875 SCV000692256 uncertain significance Atrial septal defect 2015-11-11 no assertion criteria provided clinical testing

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