ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.2474C>T (p.Pro825Leu) (rs201332554)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000249763 SCV000320236 uncertain significance Cardiovascular phenotype 2015-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (benign),Insufficient or conflicting evidence
GeneDx RCV000658971 SCV000536174 uncertain significance not provided 2018-01-18 criteria provided, single submitter clinical testing The P825L variant of uncertain significance in the MYLK gene has not been published as pathogenic or been reported as benign to our knowledge. P825L is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P825L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this substitution occurs at a position that is not conserved, and no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants.
Invitae RCV000467595 SCV000550027 uncertain significance Aortic aneurysm, familial thoracic 7 2018-06-16 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 825 of the MYLK protein (p.Pro825Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs201332554, ExAC 0.02%) but has not been reported in the literature in individuals with a MYLK-related disease. ClinVar contains an entry for this variant (Variation ID: 264351). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658971 SCV000780774 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000467595 SCV000897060 uncertain significance Aortic aneurysm, familial thoracic 7 2018-10-31 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000581201 SCV000692255 uncertain significance Marfan syndrome 2016-11-09 no assertion criteria provided clinical testing

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