Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000528941 | SCV000623681 | pathogenic | Hypertrophic cardiomyopathy | 2020-09-14 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (Invitae). In at least one individual the variant was observed to be de novo. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). A different missense substitution at this codon (p.Arg904His) has been determined to be pathogenic (PMID: 21750094, 22464770, 25448463). This suggests that the arginine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. This sequence change replaces arginine with proline at codon 904 of the MYH7 protein (p.Arg904Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. For these reasons, this variant has been classified as Pathogenic. A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). |
| Ambry Genetics | RCV002438278 | SCV002745015 | likely pathogenic | Cardiovascular phenotype | 2018-07-09 | criteria provided, single submitter | clinical testing | The p.R904P variant (also known as c.2711G>C), located in coding exon 21 of the MYH7 gene, results from a G to C substitution at nucleotide position 2711. The arginine at codon 904 is replaced by proline, an amino acid with dissimilar properties. Alternate amino acid substitutions at this position, p.R904C and p.R409H, have been reported in individuals and families with dilated cardiomyopathy (van der Zwaag PA et al. Clin. Genet., 2011 May;79:459-67; Waldmüller S et al. Eur. J. Heart Fail., 2011 Nov;13:1185-92). Internal structural analysis has also determined this position to be a hotspot location. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |