PolyPhen-HCM

PolyPhen-HCM is a method of predicting the effects of missense mutations in six genes associated with Hypertrophic Cardiomyopathy (HCM), described in Jordan, Kiezun, Baxter et al. 2011. It is currently available as a precomputed table of results for every possible variant in these six genes.

Download

Download the precomputed table of results here:

Genes and Reference Sequences

This tool currently provides predictions for variants six genes: cardiac myosin binding protein C MYBPC3, slow cardiac myosin heavy chain MYH7, slow cardiac myosin regulatory light chain MYL2, cardiac troponin I TNNI3, cardiac troponin T TNNT2, and tropomyosin alpha-1 chain TPM1. Other genes that commonly contain HCM variants are not currently available, though we are looking into providing predictions for some of them.

When looking up your variants, be sure you use the numbering from the correct reference sequence:

Gene NameNCBI protein accession
MYBPC3NP_000247.2
MYH7NP_000248.2
MYL2NP_000423.2
TNNI3NP_000354.4
TNNT2NP_001001430.1
TPM1NP_000357.3

Interpreting Your Results

Every variant will give one of 3 results:

NoCall
No prediction is made. This prediction carries no clinical significance, and should not affect your assessment of the variant at all.
Ben
The variant is predicted not to cause HCM.
Path
The variant is predicted to cause HCM.

The current version (version 1.0) has the following statistics:

See the paper (Jordan, Kiezun, Baxter et al. 2011) for details on how these numbers are calculated.

Disclaimers

This prediction is designed to be used in combination with other methods, including family segregation data and population frequency. It is not recommended to use it as the sole source of information about any variant. In accordance with the recommendations of the IARC (Plon et al. 2008) and the ACMG (Richards et al. 2008).

Although this prediction has been validated against clinical data and undergone peer review, its effectiveness as a diagnostic has not been tested in any kind of controlled clinical trial. It requires interpretation by a qualified medical professional and integration with other sources of information before being used as a diagnostic.

Citation

Please cite the following paper when using this method:

Jordan D. M., Kiezun, A., Baxter, S. M., Agarwala, V., Green, R. C., Murray, M. F., Pugh, T., Lebo, M. S., Rehm, H. L., Funke, B. H., Sunyaev, S. R. Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy. Am. J. Hum. Genet. 88, 183-92 (2011)