Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000692213 | SCV000820025 | likely pathogenic | Hypertrophic cardiomyopathy | 2022-04-12 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 247 of the MYH7 protein (p.Phe247Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 22765922, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 571159). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Phe247 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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). |
| Ambry Genetics | RCV002386201 | SCV002668380 | likely pathogenic | Cardiovascular phenotype | 2018-07-27 | criteria provided, single submitter | clinical testing | The p.F247L variant (also known as c.741C>A), located in coding exon 7 of the MYH7 gene, results from a C to A substitution at nucleotide position 741. The phenylalanine at codon 247 is replaced by leucine, an amino acid with highly similar properties. The p.F247L variant was detected in an individual with hypertrophic cardiomyopathy (HCM) and his affected relative, as well as reported in individuals from HCM cohorts with limited clinical information provided; some of these reports were documented to have an alternate nucleotide change, c.739T>C, while others did not list the specific nucleotide change associated (García-Castro M et al. Rev Esp Cardiol, 2009 Jan;62:48-56; Coto E et al. J Mol Diagn, 2012 Sep;14:518-24; Walsh R et al. Genet. Med., 2017 02;19:192-203). In addition, the c.739T>C variant has been reported to segregate with disease in a family with HCM that had testing performed at outside laboratories (personal communication). 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. |