ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.4565T>C (p.Val1522Ala) (rs763880352)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756399 SCV000884199 uncertain significance not provided 2018-01-23 criteria provided, single submitter clinical testing The MYLK c.4565T>C; p.Val1522Ala variant (rs763880352), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.004% (identified on 12 out of 277,196 chromosomes) and is classified as a variant of uncertain significance in ClinVar (ID: 409680). The valine at position 1522 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Val1522Ala variant on protein structure and function predict a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Val1522Ala variant cannot be determined with certainty.
Ambry Genetics RCV000621464 SCV000739287 uncertain significance Cardiovascular phenotype 2017-05-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770616 SCV000902067 uncertain significance Thoracic aortic aneurysm and aortic dissection 2016-11-08 criteria provided, single submitter clinical testing
Invitae RCV000467332 SCV000550007 uncertain significance Aortic aneurysm, familial thoracic 7 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1522 of the MYLK protein (p.Val1522Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs763880352, ExAC 0.01%) but has not been reported in the literature in individuals with a MYLK-related disease. 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 C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but 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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