ClinVar

Description

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 (PMID: 4942892, 678511, 26074085 ). This domain contains amino acid residues required for protein function that have been involved in pathogenic variants, such as p.Asp166Val (PMID: 12707239, 23727233, 18987303). Furthermore, an intron 6 acceptor splice site variant (c403-1G>C) causing a frameshift and replacement of the Exon 7 coded amino acids by 19 unrelated ones has been reported in the homozygous state in several individuals affected with infantile type I muscle fibre disease and cardiomyopathy, and has been shown to have a deep impact on protein function (PMID: 23365102, 27378946). This indicates that MYL2 exon 7 codes for a functionally important region of the protein. For these reasons, this variant has been classified as Pathogenic.