ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.4207C>T (p.Arg1403Cys)

gnomAD frequency: 0.00001  dbSNP: rs748559781
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000466538 SCV000550024 uncertain significance Aortic aneurysm, familial thoracic 7 2021-08-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1403 of the MYLK protein (p.Arg1403Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs748559781, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with MYLK-related conditions. 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 disruptive. 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.
GeneDx RCV002051854 SCV002319027 uncertain significance not provided 2021-10-19 criteria provided, single submitter clinical testing Has been reported in association with TAAD in published literature (Arnaud et al., 2019); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30739908)
Ambry Genetics RCV003298493 SCV003997329 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-03-20 criteria provided, single submitter clinical testing The p.R1403C variant (also known as c.4207C>T), located in coding exon 21 of the MYLK gene, results from a C to T substitution at nucleotide position 4207. The arginine at codon 1403 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in a thoracic aortic aneurysm and dissection (TAAD) cohort; however, clinical details were limited (Arnaud P et al. Genet Med, 2019 Sep;21:2015-2024). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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