Table 1.
Overview of rare heterozygous CALR3 variants identified in this study and their associated phenotypes
| Nucleotide change | Protein change | # Probands | Phenotype(s) | ExAC MAF | Splice predictiona | CADD score | M-CAP score |
|---|---|---|---|---|---|---|---|
| c.21G>C | p.(Gln7His) | 4 | HCM, DCM | 5/61010 | No effect | 0.001 | 0.004 |
| c.31A>G | p.(Ile11Val) | 1 | HCM | 1/62978 | No effect | 0.001 | 0.004 |
| c.31A>C | p.(Ile11Leu) | 3 | HCM, DCM | Absent | No effect | 0.001 | 0.004 |
| c.67T>A | p.(Phe23Ile) | 1 | HCM | 4/52406 | No effect | 31 | 0.125 |
| c.72A>G | p.(Gln24=) | 1 | HCM | Absent | Effect | 1.581 | N/A |
| c.147dup | p.(Arg50*) | 2 | DCM, LVNC | Absent | No effect | 24.6 | N/A |
| c.403G>A | p.(Asp135Asn) | 7 | HCM, DCM, LVNC, mixed | 11/108150 | No effect | 34 | 0.061 |
| c.407T>C | p.(Ile136Thr) | 2 | DCM | Absent | No effect | 27.7 | 0.059 |
| c.484A>G | p.(Arg162Gly) | 2 | HCM | Absent | No effect | 23.3 | 0.018 |
| c.520C>A | p.(Leu174Ile) | 1 | LVNC | 4/121250 | No effect | 26.2 | 0.082 |
| c.564del | p.(Gln189Serfs*8) | 17 | HCM, DCM, LVNC, mixed | 5/121312 | No effect | 7.360 | N/A |
| c.626C>T | p.(Thr209Met) | 1 | HCM | 1/121116 | No effect | 14.36 | 0.008 |
| c.801del | p.(Glu268Lysfs*13) | 1 | Mixed | Absent | No effect | 4.736 | N/A |
| c.833G>A | p.(Arg278His) | 2 | HCM, DCM | Absent | No effect | 22.3 | 0.017 |
| c.860C>T | p.(Thr287Met) | 1 | HCM | 2/121410 | No effect | 9.523 | 0.021 |
| c.1068_1069del | p.(Glu357Glyfs*12) | 1 | DCM | Absent | No effect | 35 | N/A |
| c.1094C>G | p.(Ser365Trp) | 1 | HCM | Absent | No effect | 23.3 | 0.015 |
High pathogenicity scores (CADD ≥ 20 or M-CAP > 0.025) are displayed in bold
Reference sequences: NG_031959.2, NM_145046.4 (CALR3)
CADD Combined annotation dependent depletion, DCM dilated cardiomyopathy, ExAC Exome Aggregation Consortium, HCM hypertrophic cardiomyopathy, LVNC left ventricular non-compaction, MAF minor allele frequency, M-CAP Mendelian clinically applicable pathogenicity, N/A not applicable
aSplice effect was defined as at least 10% difference between reference and mutated scores by at least 3 out of 5 mRNA splicing prediction tools (SpliceSiteFinder-like, MaxEntScan, NNSPLICE, GeneSplicer and Human Splicing Finder)