THE P.ARG230HIS VARIANT OF THE VCL PROTEIN IS NOT PATHOGENIC AND DOES NOT AFFECT HYPERTROPHIC CARDIOMYOPATHY PHENOTYPE IN RUSSIAN FAMILY CARRYING THE P.GLN1233TER PATHOGENIC VARIANT IN THE MYBPC3 GENE

Abstract

Background. Despite many years of research, the genetic basis of hypertrophic
cardiomyopathy (HCM) remains poorly understood. The rapidly accumulating data from nextgeneration sequencing have not provided answers to all the questions that have arisen. Other research
methods are needed to prove the involvement of the variants identified in pathogenesis of HCM.
Aims. We aimed to identify any specific clinical characteristics caused by a combination of
two variants, rs397516037 in the MYBPC3 gene and rs749628307 in the VCL gene, in a Russian
family of carriers and attempted to clarify whether the variant in the VCL gene contributes significantly
to the development of HCM.
Methods. The studied family included three patients with HCM and one healthy family
member. A targeted exome analysis was performed for the daughter of the proband. A structural
alignment of both forms of VCL, the canonical form and the form with p.Arg230His substitution, was
performed.
Results. The pathogenic variant, rs397516037, was detected in the proband and in several
family members. A possibly damaging variant rs749628307 was detected in the proband and several
family members investigated in this study. The structural alignment suggests that the rs749628307
variant does not alter the protein structure significantly and may not lead to impairment or loss of
function.
Conclusions. Our analysis showed that, apparently, the rs749628307 variant in the VCL gene
does not change the structure of the protein significantly or affect the severity and form of the clinical
manifestations of HCM; therefore, it could not be considered as being pathogenic