Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| CSER _CC_NCGL, |
RCV000210887 | SCV000264607 | uncertain significance | Aortic aneurysm, familial thoracic 7 | 2015-12-01 | criteria provided, single submitter | research | |
| Invitae | RCV000210887 | SCV000650552 | uncertain significance | Aortic aneurysm, familial thoracic 7 | 2022-10-07 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1431 of the MYLK protein (p.Pro1431Leu). This variant is present in population databases (rs746690413, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYLK-related conditions. ClinVar contains an entry for this variant (Variation ID: 225287). 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. 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. |
| Gene |
RCV001788070 | SCV002031063 | uncertain significance | not provided | 2023-01-06 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function |
| Fulgent Genetics, |
RCV002494549 | SCV002797702 | uncertain significance | Aortic aneurysm, familial thoracic 7; Megacystis-microcolon-intestinal hypoperistalsis syndrome 1 | 2021-08-19 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323456 | SCV004029793 | likely benign | not specified | 2023-07-05 | criteria provided, single submitter | clinical testing | Variant summary: MYLK c.4292C>T (p.Pro1431Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250898 control chromosomes (i.e., 13 heterozygotes). The observed variant frequency is approximately 1.04 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Thoracic Aortic Aneurysms And Dissections phenotype (5e-05), strongly suggesting that the variant is benign. c.4292C>T has been reported in the literature in individuals affected with Thoracic Aortic Aneurysms And Dissections (e.g., Renner_2019, Yang_2022), however without strong evidence for causality (e.g., lack of co-segregation data). These reports therefore do not provide unequivocal conclusions about association of the variant with Thoracic Aortic Aneurysms And Dissections. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30675029, 36517271). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |