Submissions for variant NM_053025.4(MYLK):c.2132C>T (p.Thr711Met)

gnomAD frequency: 0.00004  dbSNP: rs531232445

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494155	SCV000583135	uncertain significance	not provided	2017-05-12	criteria provided, single submitter	clinical testing	The T711M variant of uncertain significance in the MYLK gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T711M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and Methionine is the wild-type amino acid in multiple other species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics	RCV002314850	SCV000739322	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-03-02	criteria provided, single submitter	clinical testing	The p.T711M variant (also known as c.2132C>T), located in coding exon 12 of the MYLK gene, results from a C to T substitution at nucleotide position 2132. The threonine at codon 711 is replaced by methionine, an amino acid with similar properties, and is located in an Ig-like domain. This amino acid position is well conserved in available vertebrate species; however, methionine is the reference amino acid in other 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.
Invitae	RCV001370965	SCV001567513	uncertain significance	Aortic aneurysm, familial thoracic 7	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 711 of the MYLK protein (p.Thr711Met). This variant is present in population databases (rs531232445, gnomAD 0.007%). 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: 430348). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330726	SCV004039017	uncertain significance	not specified	2023-08-10	criteria provided, single submitter	clinical testing