ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.4336G>A (p.Glu1446Lys) (rs146682969)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617030 SCV000319403 uncertain significance Cardiovascular phenotype 2017-08-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000519483 SCV000620473 uncertain significance not provided 2018-11-08 criteria provided, single submitter clinical testing The E1446K variant of uncertain significance in the MYLK gene has not been published in association with cardiac disease to our knowledge. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In addition, this variant is observed in 34/277182 (0.012%) alleles in large population cohorts (Lek et al., 2016). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Illumina Clinical Services Laboratory,Illumina RCV000250175 SCV000440279 uncertain significance Thoracic aortic aneurysm and aortic dissection 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000469322 SCV000550030 uncertain significance Aortic aneurysm, familial thoracic 7 2018-09-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1446 of the MYLK protein (p.Glu1446Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs146682969, ExAC 0.03%) but has not been reported in the literature in individuals with a MYLK-related disease. ClinVar contains an entry for this variant (Variation ID: 263899). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function, and 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.

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