Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000599995 | SCV000713218 | likely pathogenic | Primary dilated cardiomyopathy | 2017-06-15 | criteria provided, single submitter | clinical testing | The p.Gly641Ala variant in MYH7 has been identified as apparently de novo in 1 i nfant with DCM (LMM data) and was absent from large population studies. Glycine (Gly) at position 641 is highly conserved in mammals and across evolutionarily d istant species, and the change to Alanine (Ala) was predicted to be pathogenic u sing a computational tool clinically validated by our laboratory. This tool's pa thogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Of note, this variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016). In summary, although additional studies are require d to fully establish its clinical significance, the p.Gly641Ala variant is likel y pathogenic. |
| Labcorp Genetics |
RCV001854146 | SCV002284676 | pathogenic | Hypertrophic cardiomyopathy | 2024-03-11 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 641 of the MYH7 protein (p.Gly641Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32458740). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 505801). 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%. 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). For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV005091596 | SCV005848339 | pathogenic | not provided | 2024-08-15 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32458740, 27532257, 29300372) |