ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.1133G>A (p.Arg378His) (rs56378658)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000254139 SCV000320102 uncertain significance Cardiovascular phenotype 2016-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000477018 SCV000550031 uncertain significance Aortic aneurysm, familial thoracic 7 2018-08-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 378 of the MYLK protein (p.Arg378His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs56378658, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in a single family affected with thoracic aortic aneurysms and dissections (PMID: 27146836). ClinVar contains an entry for this variant (Variation ID: 264282). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine 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.
SIB Swiss Institute of Bioinformatics RCV000477018 SCV000803574 likely benign Aortic aneurysm, familial thoracic 7 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Benign, for Aortic aneurysm, familial thoracic 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in affected members of a family (PMID:27146836). BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS2-Supporting => BS2 downgraded in strength to supporting.

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