ClinVar

Description

Variant summary: CASR c.848T>C (p.Ile283Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251332 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CASR causing Familial Hypocalciuric Hypercalcemia (0.0001 vs 0.005), allowing no conclusion about variant significance. c.848T>C has been reported in the literature in at least one heterozygous individual affected with primary hyperparathyroidism (e.g. Guarnieri_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypocalciuric Hypercalcemia. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g.Guarnieri_2010). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=6) or pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.