ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.1786G>A (p.Ala596Thr)

gnomAD frequency: 0.00007  dbSNP: rs758715543
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000529369 SCV000650516 uncertain significance Aortic aneurysm, familial thoracic 7 2023-12-03 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 596 of the MYLK protein (p.Ala596Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with aortic dissection and/or dilatation (Invitae). ClinVar contains an entry for this variant (Variation ID: 471704). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Ambry Genetics RCV002315006 SCV000739282 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2020-12-07 criteria provided, single submitter clinical testing The p.A596T variant (also known as c.1786G>A), located in coding exon 10 of the MYLK gene, results from a G to A substitution at nucleotide position 1786. The alanine at codon 596 is replaced by threonine, an amino acid with some similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000529369 SCV002768364 uncertain significance Aortic aneurysm, familial thoracic 7 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial thoracic aortic aneurysm, 7 (MIM#613780). (I) 0108 - This gene is associated with both recessive and dominant disease. This gene is associated with autosomal dominant familial thoracic aortic aneurysm, 7 (MIM#613780) although homozygous carriers with more early-onset severe disease have also been reported, and autosomal recessive megacystis-microcolon-intestinal hypoperistalsis syndrome (MIM#249210) (PMID: 29544503; OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 29544503; OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 29544503). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0219 - This variant is non-coding in an alternative transcript. This variant is non-coding in the NM_053031.4 and NM_053032.4 transcripts. Although these transcripts are more widely expressed than our chosen transcript, the variant is located in an exon (exon 13) which has increased expression in the aorta, our tissue of interest, compared to other tissues (UCSC, GTEx). (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (10 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Ig-like C2-type 4 domain (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS in Clinvar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV002315006 SCV003838272 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2021-06-11 criteria provided, single submitter clinical testing
GeneDx RCV001528641 SCV004022817 uncertain significance not provided 2023-07-26 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001528641 SCV001740719 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001528641 SCV001971015 uncertain significance not provided no assertion criteria provided clinical testing

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