Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000156695 | SCV000206416 | uncertain significance | not specified | 2014-07-17 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The Phe252Ser v ariant in MYH7 has not been previously reported in individuals with cardiomyopat hy or in large population studies. Phenylalanine (Phe) at position 252 is conser ved in mammals (with the exception of turkey) and across evolutionarily distant species and the change to Serine (Ser) was predicted to be pathogenic using a co mputational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the Phe252Ser variant is uncertain. |
| Invitae | RCV001219303 | SCV001391236 | likely pathogenic | Hypertrophic cardiomyopathy | 2023-11-13 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 252 of the MYH7 protein (p.Phe252Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy and/or restrictive cardiomyopathy (PMID: 25422285; Invitae). ClinVar contains an entry for this variant (Variation ID: 179894). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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. |
| 3billion | RCV003313940 | SCV004013612 | likely pathogenic | Hypertrophic cardiomyopathy 1 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 29300372). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYH7 related disorder (PMID: 24093860). Different missense changes at the same codon (p.Phe252Cys, p.Phe252Leu) have been reported to be associated with MYH7 related disorder (ClinVar ID: VCV000217472 / PMID: 18506004, 27247418). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. |