Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000820310 | SCV000961018 | uncertain significance | Hypertrophic cardiomyopathy | 2023-10-04 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 38 of the MYH7 gene. It does not directly change the encoded amino acid sequence of the MYH7 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 662627). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.5655+5G nucleotide in the MYH7 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 30794915). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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. |
| Institute of Human Genetics, |
RCV003882734 | SCV004697522 | pathogenic | Myosin storage myopathy | 2024-01-31 | criteria provided, single submitter | clinical testing | |
| Kardio |
RCV004822232 | SCV005442800 | likely pathogenic | Dilated cardiomyopathy 1S | 2024-12-03 | criteria provided, single submitter | clinical testing | The detected MYH7 variant is a nucleotide exchange located near the donor splice site in intron 38. According to bioinformatics prediction, this variant is expected to disrupt splicing, leading to exon skipping of exon 38. In the ClinVar database, there are two entries regarding this variant: One from 2023, which classifies it as of "unclear clinical significance" in the context of hypertrophic cardiomyopathy, and another one from 2024, which classifies it as pathogenic in relation to myosin storage myopathy. No data on the allele frequency of this variant in the general population from the gnomAD database is available. A strong criterion for the pathogenicity of the MYH7 variant c.5655+5G>A is the classification of a variant located at the same nucleotide position, c.5655+5G>C, as pathogenic (Surikova et al.). A 4-year-old boy with congenital muscle weakness, who carries the de novo splice variant c.5655+5G>C, was described. This boy was diagnosed with left ventricular dilation at seven months of age. RNA analysis from a muscle biopsy confirmed in-frame exon skipping of MYH7 exon 38, as well as a functional minigene assay in HEK293 cells – conducted with other variants also described as de novo in the splice region. Finally, Surikova et al. generalize their observation that variants causing exon 38 skipping lead to a particular phenotype, characterized by congenital myopathy with an unusually early onset, axial hypotonia, and the so-called dropped-head syndrome. The authors further speculate that the donor splice region of exon 38 of the MYH7 gene may represent a hotspot for de novo pathogenic variants. PS1, PM2_supporting, PP3 |