Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000035803 | SCV000059454 | likely pathogenic | Hypertrophic cardiomyopathy | 2015-04-01 | criteria provided, single submitter | clinical testing | The p.Met849Thr variant in MYH7 has been reported in 1 individual with end-stage HCM (Garcia-Pavia) and was identified by our laboratory as a de novo occurrence in 1 Caucasian adult with HCM. This variant was absent from large population st udies. Methionine (Met) at position 849 is not well conserved in evolution; howe ver the change to threonine (Thr) was predicted to be pathogenic using a computa tional tool clinically validated by our laboratory. This tool's pathogenic predi ction is estimated to be correct 94% of the time (Jordan 2011). In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Met849Thr variant is likely pathogenic. |
| Blueprint Genetics | RCV000788450 | SCV000927569 | likely pathogenic | not provided | 2018-03-06 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000035803 | SCV001577616 | likely pathogenic | Hypertrophic cardiomyopathy | 2022-08-16 | criteria provided, single submitter | clinical testing | 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). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). ClinVar contains an entry for this variant (Variation ID: 42914). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 21896538, 26914223, 27532257, 29121657; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 849 of the MYH7 protein (p.Met849Thr). |
| Ambry Genetics | RCV002426554 | SCV002742502 | likely pathogenic | Cardiovascular phenotype | 2022-01-05 | criteria provided, single submitter | clinical testing | The p.M849T variant (also known as c.2546T>C), located in coding exon 20 of the MYH7 gene, results from a T to C substitution at nucleotide position 2546. The methionine at codon 849 is replaced by threonine, an amino acid with similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM) and showed co-segregation in an affected relative in one family; clinical details were limited in some cases (Garcia-Pavia P et al. Eur J Heart Fail, 2011 Nov;13:1193-201; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Chida A et al. Heart Vessels, 2017 Jun;32:700-707; Lorenzini M et al. J Am Coll Cardiol, 2020 08;76:550-559; Viswanathan SK et al. PLoS One, 2017 Nov;12:e0187948). This variant was also detected in two individuals from HCM genetic testing cohorts (Walsh R et al. Genet Med, 2017 02;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well 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. |