Total submissions: 2
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. |
Invitae | RCV001854146 | SCV002284676 | likely pathogenic | Hypertrophic cardiomyopathy | 2021-11-26 | 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 505801). 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. This variant is not present in population databases (gnomAD no frequency). 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). |