ClinVar

Description

The Met149Val mutation in the MYL3 gene has been published in association with HCM (Poetter K et al., 1996; Arad M et al., 2005). Poetter et al. reported Met149Val to co-segregate with HCM in one family, and did not detect the mutation in 378 control chromosomes from healthy individuals. Six of the 13 family members with HCM had a phenotype involving mid left ventricular chamber (MVC) thickening apparent in a left ventriculogram (Poetter K et al., 1996). Additionally, this study performed in vitro motility assays and demonstrated that myosin from patients with the Met149Val mutation translocated actin filaments somewhat faster than the control myosin. Arad et al. reported the Met149Val mutation in a 23 year old individual with HCM, who presented with palpitations. Previous clinical evaluations in this individual's relatives identified apical HCM in 5 individuals, and typical asymmetrical hypertrophy of the anterior basal septum in 6 individuals. Two other individuals in the family were reported to have heart failure, and 3 others had sudden death. Although Met149Val results in a conservative amino acid replacement of one non-polar residue for another, the Met149 residue is highly conserved across species. Mutations affecting nearby codons (Glu143Lys, Gly152Lys, Arg154His) have been reported in association with HCM, further supporting the functional importance of this region of the protein. In silico analysis predicts this change to be probably damaging to the structure/function of the protein. Furthermore, Met149Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Of note, studies performed on transgenic rabbits harboring the Met149Val mutation in the MYL3 gene failed to recapitulate an HCM phenotype (James J et al., 2002). However, the authors acknowledged the association of Met149Val with HCM in humans and noted that the conflicting data may be due to the young age of the animals used. In summary, Met149Val in the MYL3 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).