Submissions for variant NM_053025.4(MYLK):c.149C>T (p.Ala50Val)

gnomAD frequency: 0.00006  dbSNP: rs369576521

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489357	SCV000576615	uncertain significance	not provided	2022-10-21	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 does not alter protein structure/function
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769346	SCV000900730	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-04-08	criteria provided, single submitter	clinical testing
Invitae	RCV001851307	SCV002241093	uncertain significance	Aortic aneurysm, familial thoracic 7	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 50 of the MYLK protein (p.Ala50Val). This variant is present in population databases (rs369576521, gnomAD 0.05%). 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: 426226). 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 95%. 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.
Institute of Human Genetics, University Hospital Muenster	RCV001851307	SCV002496142	uncertain significance	Aortic aneurysm, familial thoracic 7	2022-01-20	criteria provided, single submitter	clinical testing	ACMG categories: PM1,BP1
Ambry Genetics	RCV000769346	SCV002702290	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-03-25	criteria provided, single submitter	clinical testing	The p.A50V variant (also known as c.149C>T), located in coding exon 1 of the MYLK gene, results from a C to T substitution at nucleotide position 149. The alanine at codon 50 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000489357	SCV004155433	uncertain significance	not provided	2022-03-01	criteria provided, single submitter	clinical testing