SUN-780 A Novel CASR Missense Variant c.2015C>T Identified as a Cause of Familial Hypocalciuric Hypercalcemia

Abstract Disclosure: B.R. Dillon: None. A.K. Petersen: None. M. Sum: None. Background: PTH-mediated hypercalcemia requires consideration of the diagnosis of familial hypocalciuric hypercalcemia (FHH), especially in patients younger than 30 years old, with a family history of hypercalcemia, and whose hypercalcemia is lifelong. While a urinary calcium-creatinine clearance ratio less than 0.01 supports a diagnosis of FHH rather than primary hyperparathyroidism (PHPT), it cannot reliably differentiate between the two. Clinical Case: A 26-year-old man presented with chronic, incidental hypercalcemia since age 23 ranging from 10.9 to 12.2 mg/dL (normal 8.4-10.2 mg/dL) and inappropriately normal or elevated PTH levels of 32.2 to 104.2 pg/mL (normal 18.5-88.0 pg/mL). He reported mild heartburn with occasional calcium carbonate use. He denied history of constipation, nephrolithiasis, and fracture. He reported hypercalcemia in his brother and osteoporosis in his father. Further investigation demonstrated a 25-OH vitamin D level of 26 ng/mL (normal 15-90 ng/mL), a low urinary calcium-creatinine clearance ratio of 0.005, an unremarkable renal ultrasound, and a normal bone mineral density. Genetic testing was pursued and identified a heterozygous variant in the CASR gene sequence at nucleotide c.2015 in exon 7 resulting in replacement of proline by leucine at codon 672 (c.2015C>T, p.Pro672Leu) deemed likely pathogenic (Fulgent Therapeutics LLC, hyperparathyroidism—8 gene panel, NGS). Indeed, another variant (c.2014C>A, p.Pro672Thr) at the same codon has been identified as pathogenic, with an inactivating effect on the calcium-sensing receptor. In both our novel variant and the reported variant, the mutation shifts the codon from the cyclic proline to an acyclic linear structure with a side chain—leucine and threonine, respectively. A diagnosis of FHH was made and parathyroidectomy was not pursued. Genetic testing for his immediate family members was recommended. Conclusion: We report identification of a novel missense variant c.2015C>T in a functional domain of the CASR gene in a 26-year-old man with asymptomatic mild to moderate hypercalcemia, in which a diagnosis of FHH was made. In comparison to PHPT, FHH is a rare cause of hypercalcemia for which no medical or surgical treatment is usually needed. Our novel reported variant adds to the case literature for a condition in which genetic testing often guides diagnosis confirmation and management decisions. References: 1. Bilezikian JP, Khan AA, Silverberg SJ, et al. Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop. Journal of Bone and Mineral Research. 2020;37(11):2293-2314. 2. Charoenngam N, Wattanachayakul P, Mannstadt M. CASRdb: A Publicly Accessible Comprehensive Database for Disease-associated Calcium-sensing Receptor Variants. The Journal of Clinical Endocrinology & Metabolism. 2024:dgae769. Presentation: Sunday, July 13, 2025