Submissions for variant NM_000388.4(CASR):c.661C>T (p.Pro221Ser)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994928	SCV004813571	pathogenic	Autosomal dominant hypocalcemia	2024-02-01	criteria provided, single submitter	clinical testing	Variant summary: CASR c.661C>T (p.Pro221Ser) results in a non-conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250832 control chromosomes. c.661C>T has been reported in the literature in multiple individuals from a large family with familial hypocalciuric hypercalcaemia with recurrent pancreatitis and segregated with disease (example, Pearce_1996). These data indicate that the variant is very likely to be associated with Autosomal Dominant Hypocalcemia. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about twice higher EC50[Ca2+]o of WT CASR in HEK cells (Pearce_1996). The following publications have been ascertained in the context of this evaluation (PMID: 9039332, 8878438). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic.