ClinVar

Description

0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene and are associated with CASR-related disease (OMIM). Truncating variants predicted to undergo nonsense-mediated decay, and missense variants with either a dominant negative or loss of function effect on protein function, have been reported to cause hypocalciuric hypercalcemia, type I (MIM#145980), and neonatal hyperparathyroidism (MIM#239200). Missense variants that have a gain of function effect on protein activity, have been reported to cause hypocalcemia, with or without Barrter syndrome (MIM#601198) (OMIM, PMID: 22422767, PMID: 26646938, PMID: 16649980). (I) 0108 - This gene is associated with both recessive and dominant disease. Recessive disease is caused by biallelic loss of function variants, and results in neonatal hyperparathyroidism (MIM#239200) (OMIM, PMID: 22422767, PMID: 26646938). (I) 0115 - Variants in this gene are known to have variable expressivity. Members of the same family have been reported to exhibit either hypercalcemia, hypocalciuric or hypercalciuric (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ligand binding domain (PDB, NCBI). Protein modelling has indicated that an agonist is expected to form a hydrogen bond with this residue (PMID: 32387992). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. Nearby missense variants (p.Arg66Cys, p.Arg66His, p.Cys60Tyr) have been reported as pathogenic and in patients with recessive disease (ClinVar, PMID: 33179231). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign