MYL2 in Hypertrophic Cardiomyopathy (HCM)

The role of rare variants in MYL2 as causative mutations in Hypertrophic Cardiomyopathy is described below. By comparing the frequency of MYL2 variants in large HCM clinical cohorts to the background population rate in the ExAC database, the proportion of HCM patients with pathogenic mutations in MYL2 can be estimated, as well as the likelihood that a rare (population allele frequency <0.0001) MYL2 variant identified in a HCM patient is disease-causing. Summary data for different variant classes (all protein-altering variants, loss of function truncating variants and non-truncating variants) is highlighted - see the table below for full details of this analysis.

Excess of MYL2 variants in HCM: 0.92% (p<0.0001)

Based on an analysis of all rare protein-altering variants (MAF<0.0001 in ExAC) in MYL2 found in 4185 HCM samples sequenced by OMGL and LMM and in reference samples of the ExAC population database.

Metrics by Variant Class:

	All Vars	Truncating	Non-Truncating
Excess in HCM	0.92% p<0.0001	0.05% p=0.0932	0.87% p<0.0001
Etiological fraction	0.84 0.77 - 0.89	0.68 0.00 - 0.91	0.85 0.78 - 0.90
Odds Ratio	6.27 4.33 - 8.96	3.10 0.57 - 11.11	6.74 4.58 - 9.80

The Etiological Fraction (EF) is the proportion of affected carriers where the variant caused HCM. The Odds Ratio (OR) describes the odds of having a rare variant in the patient cohort to the odds in the ExAC cohort. Fisher's exact test p-values are displayed for case excess, 95% confidence intervals for EFs and ORs.

Source	Samples Tested	Variant Type	Variants detected	Frequency in HCM	Frequency in ExAC	Case Excess in HCM
Combined (OMGL1 + LMM2)	4185	All	46	0.01099	0.00176	0.00923
		Truncating	3	0.00072	0.00024	0.00048
		Non-Truncating	43	0.01027	0.00154	0.00873

OMGL1	1535	All	11	0.00717	0.00176	0.00541
		Truncating	1	0.00065	0.00024	0.00041
		Non-Truncating	10	0.00651	0.00154	0.00497

LMM2	2650	All	35	0.01321	0.00176	0.01145
		Truncating	2	0.00075	0.00024	0.00051
		Non-Truncating	33	0.01245	0.00154	0.01091

References

1. Roddy Walsh, Kate L. Thomson, James S. Ware, Birgit H. Funke, Jessica Woodley, Karen J. McGuire, Francesco Mazzarotto, Edward Blair, Anneke Seller, Jenny C. Taylor, Eric V. Minikel, Exome Aggregation Consortium, Daniel G. MacArthur, Martin Farrall, Stuart A. Cook and Hugh Watkins. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2016 doi:10.1038/gim.2016.90.

2. Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, Shen J, McLaughlin HM, Clark EH, Babb LJ, Cox SW, DePalma SR, Ho CY, Seidman JG, Seidman CE, Rehm HL. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015 Nov;17(11):880-8.