ClinVar

Description

In summary, this variant deletes the last exon of the protein where amino acids important for protein function have been reported. However, further genetic and/or functional evidence is necessary to classify this variant conclusively. For these reasons, it has been classified as a Variant of Uncertain Significance. This variant is a gross deletion of the genomic region encompassing exon 7 of the MYL2 gene. The 5' boundary is likely confined to intron 6. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. This variant results in the deletion of the EF-hand calcium binding domain 3 that is a conserved region involved in calcium binding (PMID: 4942892, 678511, 26074085). An intron 6 acceptor splice site pathogenic variant (c.403-1G>C) has been reported in the homozygous state in several individuals affected with infantile type I muscle fibre disease and cardiomyopathy, while the heterozygous relatives were apparently unaffected (PMID: 23365102, 27378946). In addition, a missense substitution in this region (p.Asp166Val) has been determined to be likely pathogenic (PMID: 12707239, 23727233, 18987303). This suggests that the aspartic acid residue is critical for MYL2 protein function and that deleting it may be deleterious. This variant has not been reported in the literature in individuals affected with a MYL2-related disease.