Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000035747 | SCV000059398 | likely pathogenic | Hypertrophic cardiomyopathy | 2018-05-25 | criteria provided, single submitter | clinical testing | The p.Val586Ala variant in MYH7 has been identified in 2 individuals with HCM a nd segregated with disease in 3 affected relatives from one family (LMM data). I t has not been identified in large population studies. Computational prediction tools and conservation analysis suggest that the p.Val586Ala variant may impact the protein, though this information is not predictive enough to determine patho genicity. 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 mo re likely to cause disease (Walsh 2016). The above evidence supports a pathogeni c role; however, it should be noted that 6 reportedly unaffected family members (29 years and older) carried the variant, suggesting clinical variability or red uced penetrance. In summary, although additional studies are required to fully e stablish its clinical significance, the p.Val586Ala variant is likely pathogenic . ACMG/AMP Criteria applied: PM1, PM2, PP1, PP3, PS4_Supporting. |
| Invitae | RCV000035747 | SCV001383676 | uncertain significance | Hypertrophic cardiomyopathy | 2019-08-23 | criteria provided, single submitter | clinical testing | 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42865). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 586 of the MYH7 protein (p.Val586Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |