ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.3121G>A (p.Ala1041Thr)

gnomAD frequency: 0.00001  dbSNP: rs568590920
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000472877 SCV000550045 uncertain significance Aortic aneurysm, familial thoracic 7 2023-11-14 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1041 of the MYLK protein (p.Ala1041Thr). This variant is present in population databases (rs568590920, gnomAD 0.006%). This missense change has been observed in individual(s) with thoracic aortic aneurysm and/or dissection (PMID: 29907982). ClinVar contains an entry for this variant (Variation ID: 409711). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYLK protein function with a negative predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics RCV002480415 SCV000897058 uncertain significance Aortic aneurysm, familial thoracic 7; Megacystis-microcolon-intestinal hypoperistalsis syndrome 1 2021-09-01 criteria provided, single submitter clinical testing
GeneDx RCV001552695 SCV001773431 uncertain significance not provided 2021-10-04 criteria provided, single submitter clinical testing Has been reported in an individual with TAA, aortic root dilation, and bicuspid aortic valve (BAV) in published literature (Overwater et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 409711; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 29907982)
PreventionGenetics, part of Exact Sciences RCV003418191 SCV004108685 uncertain significance MYLK-related condition 2023-08-01 criteria provided, single submitter clinical testing The MYLK c.3121G>A variant is predicted to result in the amino acid substitution p.Ala1041Thr. This variant was reported as variant of unknown significance in an individual suspected of heritable thoracic aortic disorder (Table S1, Overwater et al. 2018. PubMed ID: 29907982). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-123419194-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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