ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.257G>A (p.Arg86Gln) (rs138265409)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000727292 SCV000884202 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing The MYLK c.257G>A; p.Arg86Gln variant (rs138265409, ClinVar variant ID 264174), 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 0.03% (identified on 8 out of 24,028 chromosomes). The arginine at position 86 is weakly conserved, considering 12 species, and computational analyses of the effects of the p.Arg86Gln variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: probably damaging). Based on the available information, the clinical significance of the p.Arg86Gln variant cannot be determined with certainty.
Ambry Genetics RCV000617085 SCV000319909 uncertain significance Cardiovascular phenotype 2016-02-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727292 SCV000707299 uncertain significance not provided 2017-04-06 criteria provided, single submitter clinical testing
GeneDx RCV000727292 SCV000573793 uncertain significance not provided 2018-06-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYLK gene. The R86Q variant has not been published as pathogenic or been reported as benign to our knowledge. This variant has been observed in other individuals referred for HDCT genetic testing at GeneDx, although no segregation data are available to further clarify the role of this variant in disease. Additionally, this variant is observed at a global allele frequency of 25/276950 (0.009%) alleles in large population cohorts, including 8/24028 (0.03%) alleles from individuals of African ancestry (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, R86Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties.
Illumina Clinical Services Laboratory,Illumina RCV000247571 SCV000440349 uncertain significance Thoracic aortic aneurysm and aortic dissection 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000554596 SCV000650529 uncertain significance Aortic aneurysm, familial thoracic 7 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 86 of the MYLK protein (p.Arg86Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs138265409, 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: 264174). 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 C35"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.

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