Table 3.
Relatedness of Heterozygous Carriers of Rare Nonsense, Frameshift, and Missense Variants in CASR, and Serum Ca, Albumin-Corrected Serum Ca Values, Urinary Ca, and Serum for Heterozygous Individuals in the 92K DiscovEHR Cohort
| Variant | Age (year) | Sex | Mean Serum Ca mg/dLa(# measures) | Median Serum Caalbmg/dL | Mean Urinary Ca gb(# measures) | PTH pg/mLc(# measures) | Relatednessd | Pi-HAT |
|---|---|---|---|---|---|---|---|---|
| Nonsense/Frameshift Variants | ||||||||
| p.Leu37Alafs∗11 | 44 | M | 10.3 ± 0.23 (3) | 10.4 | N/A | N/A | proband∗ | 0.5 |
| p.Leu37Alafs∗11 | 61 | F | 10.5 ± 0.35 (12) | 10.4 | 0.23(1) | 139.4 (8) | parent∗ | |
| p.Leu37Alafs∗11 | 74 | M | 10.7 ± 0.4 (23) | 10.7 | N/A | 127.4 ± 48 (6) | proband∗ | 0.5304 |
| none | 77 | F | 9.93 ± 0.37 (28) | 10.0 | N/A | 47.5 ± 9.3 (4) | full sibling | |
| p.Cys101∗ | 33 | F | 10.2 ± 0.4 (7) | 10.4 | N/A | N/A | proband∗ | 0.2537 |
| p.Cys101∗ | 83 | M | 10.9 ± 0.4 (28) | 10.9 | 0.171 (1) | 47.6 ± 27 (11) | 2°∗ | |
| p.Arg227∗ | 65 | F | 10.5 ± 0.44 (28) | 10.4 | 0.057 (1) | 73.6 ± 16 (5) | proband∗ | |
| none | 90 | F | 9.83 ± 0.4 (53) | 9.9 | N/A | N/A | parent | 0.5 |
| none | 47 | M | 9.7 ± 0.3 (8) | 9.6 | N/A | N/A | child | 0.5 |
| none | 71 | F | 9.6 ± 0.4 (28) | 9.5 | N/A | N/A | full sibling | 0.5578 |
| p.Arg227∗ | 45 | M | 10.13 ± 0.4 (8) | 10.2 | N/A | 45 (1) | proband∗ | 0.2513 |
| none | 55 | M | 9.49 ± 0.53 (19) | 9.6 | N/A | 18 (1) | 2° | |
| p.Arg227∗ | 68 | M | 9.95 ± 0.4 (24) | 10 | N/A | 146.5 ± 13 (2) | proband∗ | 0.5112 |
| none | 63 | F | 9.32 ± 0.2 (11) | 9.3 | N/A | 41.5 ± 21.5 (2) | full sibling | |
| p.Pro1025Argfs∗9 | 64 | F | 9.67 ± 0.34 (9) | 9.7 | N/A | N/A | proband∗ | |
| none | 81 | F | 9.64 ± 0.3 (12) | 9 | N/A | N/A | parent | 0.5142 |
| none | 84 | M | 9.22 ± 0.3 (32) | 9.2 | N/A | N/A | 2° | 0.2413 |
| none | 32 | F | 9.3 ± 0.35 (3) | 9.1 | N/A | N/A | 2° | 0.2889 |
| p.Pro1025Argfs∗9 | 74 | F | 10.1 ± 0.3 (27) | 10.2 | N/A | 42.8 ± 9.8 (4) | proband∗ | |
| none | 27 | M | 9.7 (1) | 9.7 | N/A | N/A | 2° | 0.299 |
| none | 29 | M | 9.68 ± 0.39 (12) | 9.5 | N/A | N/A | 2° | 0.2142 |
| p.Pro1025Argfs∗9 | 81 | F | 9.64 ± 0.3 (25) | 9.6 | N/A | 56 (1) | proband∗ | |
| none | 84 | M | 9.22 ± 0.3 (32) | 0.2 | N/A | N/A | full sibling | 0.4886 |
| none | M | 63 | 9.28 ± 0.35 (5) | 9.1 | N/A | 47.3 ± 16 (4) | 2° | 0.2455 |
| none | 32 | F | 9.3 ± 0.4 (3) | 9.1 | N/A | N/A | 2° | 0.2917 |
| Missense Variants | ||||||||
| p.Asp23Glu | 64 | M | 8.25 ± 0.4 (18) | 8.3 | N/A | N/A | proband∗ | 0.5787 |
| none | 69 | M | 9.0 ± 0.3 (9) | 9 | N/A | N/A | full sibling | |
| p.Leu322Pro | 56 | F | 8.39 ± 0.4 (154) | 8.4 | N/A | 30.2 ± 13 (10) | proband∗ | |
| p.Leu322Pro | 79 | M | 8.6 ± 0.9 (54) | 8.3 | N/A | 14 ± 6.1 (9) | parent∗ | 0.4946 |
| none | 77 | F | 9.95 ± 0.5 (29) | 10 | N/A | 33 (1) | parent | 0.4977 |
| p.Ala19Pro | 69 | M | 10.23 ± 0.41 (10) | 10.2 | N/A | N/A | proband∗ | 0.5093 |
| p.Ala19Pro | 40 | F | 10.2 ± 0.3 (8) | 10.1 | N/A | N/A | child∗ | |
| pAla19Pro | 35 | F | 10.3 | 10.3 | N/A | N/A | proband∗ | 0.1918 |
| none | 79 | M | 9.01 ± 0.34 (10) | 9 | N/A | N/A | 2° | |
| p.Arg66His | 60 | F | 10.44 ± 0.3 (4) | 10.5 | N/A | N/A | proband∗ | 0.2425 |
| p.Arg66His | 70 | M | 10 ± 0.3 (61) | 10 | N/A | N/A | 2°∗ | |
| p.Cys395Arg | 65 | F | 10.84 ± 0.4 (16) | 10.9 | 0.1 (1) | 49.5 ± 17 (11) | proband∗ | 0.5 |
| p.Cys395Arg | 40 | F | 10.94 ± 0.5 (9) | 10.9 | 0.13 ± 0.02 (2) | 29 ± 7.4 (9) | child∗ | |
| none | 60 | M | 9.4 ± 0.24 (4) | 9.2 | N/A | N/A | 2° | 0.1898 |
| p.Glu399Asp | 55 | F | 10.2 ± 0.4 (5) | 10.4 | N/A | N/A | proband∗ | 0.1893 |
| none | M | 65 | 9.2 ± 0.24 (6) | 9.2 | N/A | N/A | 2° | |
| p.Ser417Cys | 65 | M | 10.4 ± 0.6(5) | 10.3 | N/A | N/A | proband∗ | 0.5037 |
| none | 66 | F | 9.29 ± 0.33 (9) | 9.3 | N/A | N/A | full sibling | |
| p.Ser417Cys | 55 | M | 10.13 ± 0.33 (24) | 10.1 | N/A | 12.5 ± 3.4 (2) | proband∗ | |
| p.Ser417Cys | 90 | F | 10.1 ± 0.3 (18) | 10.1 | N/A | 40 (1) | 2°∗ | 0.298 |
| none | 74 | M | 9.18 ± 0.23 (11) | 9.2 | N/A | N/A | full sibling | 0.5272 |
| p.Leu660Pro | 45 | F | 10.5 (1) | 10.5 | N/A | N/A | proband∗ | 0.2201 |
| p.Leu660Pro | 65 | F | 10.9 ± 0.4 (27) | 10.9 | 0.06 ± 0.03 (2) | 43.7 ± 7.8 (9) | 2°∗ | |
| p.Arg690Cys | 76 | F | 9.87 ± 0.4 (27) | 10 | N/A | N/A | proband∗ | 0.3389 |
| none | 55 | M | 9.14 ± 0.44 (4) | 9.1 | N/A | N/A | 2° | |
N/A, no measures in EHR. Parent-Child (P-C), full sibling, or 2° (unspecified) relations are listed. Genomic variants are designated relative to the CASR reference sequence (GenBank: NM_001178065.2).
a
Normal range for serum Ca is 8.5–10.2 mg/dL.
b
Normal range for urinary Ca is 0.1–0.25 g/24 h.
c
Reference range for serum PTH is 10–65 pg/mL.
d
Asterisk indicates variant carrier.