ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.2462+5G>A (rs374003770)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000598662 SCV000710748 uncertain significance not provided 2019-01-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYLK gene. The c.2462+5 G>A variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 15/126,610 (0.012%) alleles from individuals of European (Non-Finnish) ancestry large population cohorts (Lek et al., 2016). In-silico splice site analyses suggest that this variant weakens or destroys the splice donor site in intron 17 and may lead to abnormal gene splicing. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Of note, only one other splice site variant in the MYLK gene has been reported in the Human Gene Mutation Database in association with autosomal recessive MMIHS, and most variants reported in the MYLK gene in association with autosomal dominant TAAD are missense variants (Stenson et al., 2014).
Invitae RCV000707577 SCV000836678 uncertain significance Aortic aneurysm, familial thoracic 7 2018-11-20 criteria provided, single submitter clinical testing This sequence change falls in intron 17 of the MYLK gene. It does not directly change the encoded amino acid sequence of the MYLK protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs374003770, ExAC 0.01%). This variant has not been reported in the literature in individuals with MYLK-related disease. ClinVar contains an entry for this variant (Variation ID: 504425). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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