Submissions for variant NM_033118.4(MYLK2):c.557C>T (p.Thr186Met)

gnomAD frequency: 0.00004  dbSNP: rs727504591

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155764	SCV000205475	uncertain significance	not specified	2013-06-05	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Thr186Met varia nt in MYLK2 has not been reported in individuals with cardiomyopathy or in large population studies. Threonine (Thr) at position 186 is not well conserved in ev olution and several mammals (bushbaby, megabat and sloth) have a methionine (Met ) at this position, suggesting that this change may be tolerated. Additional com putational analyses (AlignGVGD, PolyPhen2, and SIFT) do not suggest a high likel ihood of impact to the protein. In summary, the lack of conservation and presenc e of this variant in other species suggests that this variant may be benign, but additional studies are needed to fully assess the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155764	SCV001431989	likely benign	not specified	2020-08-10	criteria provided, single submitter	clinical testing	Variant summary: MYLK2 c.557C>T (p.Thr186Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251046 control chromosomes (gnomAD). The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK2 causing Hypertrophic Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.557C>T in individuals affected with Hypertrophic Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV001753545	SCV002007608	uncertain significance	not provided	2022-10-06	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 does not alter protein structure/function
Invitae	RCV001850133	SCV002173860	uncertain significance	Hypertrophic cardiomyopathy 1	2023-05-08	criteria provided, single submitter	clinical testing	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. 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 MYLK2 protein function. ClinVar contains an entry for this variant (Variation ID: 178986). This variant has not been reported in the literature in individuals affected with MYLK2-related conditions. This variant is present in population databases (rs727504591, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 186 of the MYLK2 protein (p.Thr186Met).
Ambry Genetics	RCV002345507	SCV002650041	uncertain significance	Inborn genetic diseases	2021-07-18	criteria provided, single submitter	clinical testing	The p.T186M variant (also known as c.557C>T), located in coding exon 3 of the MYLK2 gene, results from a C to T substitution at nucleotide position 557. The threonine at codon 186 is replaced by methionine, 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.